TW202506137A - Lrrk2-modulating compositions and methods of use thereof - Google Patents

Abstract

Aspects of the disclosure provide compounds, compositions, and methods for modulating the expression or activity of leucine-rich repeat kinase 2 (LRRK2). In some aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of LRRK2 mRNA in a cell or animal. In some aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of LRRK2 protein in a cell or animal.

Description

Translated fromChinese

LRRK2調節組合物及其使用方法LRRK2 modulating compositions and methods of use thereof

本揭示案提供用於調節富白胺酸重複激酶2 (LRRK2)之表現或活性之化合物、組合物及方法。在某些實施例中，該等化合物、組合物及方法可用於降低細胞或動物中LRRK2 mRNA之表現。在某些實施例中，該等化合物、組合物及方法可用於減少細胞或動物中LRRK2蛋白之量。The present disclosure provides compounds, compositions and methods for modulating the expression or activity of leucine-rich repeat kinase 2 (LRRK2). In certain embodiments, the compounds, compositions and methods can be used to reduce the expression of LRRK2 mRNA in cells or animals. In certain embodiments, the compounds, compositions and methods can be used to reduce the amount of LRRK2 protein in cells or animals.

在某些實施例中，動物患有CNS相關之疾病、病症或疾患。在某些實施例中，疾病、病症或疾患為神經退化性疾病，包括帕金森氏病(Parkinson’s Disease)。本文所提供之某些化合物、組合物及方法係關於減少動物的CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害，或諸如運動功能喪失、聚集體形成及神經元死亡之症狀。在某些實施例中，本文所提供之化合物及組合物係強效且可耐受的，且抑制LRRK2表現，該等化合物及組合物可用於治療、預防、改善CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害，或諸如運動功能喪失、聚集體形成及神經元死亡之症狀，或減緩其進展。In certain embodiments, the animal suffers from a CNS-related disease, disorder or condition. In certain embodiments, the disease, disorder or condition is a neurodegenerative disease, including Parkinson's Disease. Certain compounds, compositions and methods provided herein are directed to reducing a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof in an animal, including Parkinson's disease or cognitive impairment, or symptoms such as loss of motor function, aggregate formation and neuronal death. In certain embodiments, the compounds and compositions provided herein are potent and tolerable, and inhibit LRRK2 expression, and can be used to treat, prevent, improve, or slow the progression of CNS-related diseases, disorders, or conditions or symptoms thereof, or neurodegenerative diseases or symptoms thereof, including Parkinson's disease or cognitive impairment, or symptoms such as motor function loss, aggregate formation, and neuronal death.

在某些實施例中，該等化合物及組合物包含一或多種有效增加效能之特徵。在某些實施例中，該等化合物及組合物包含一或多種有效增加耐受性之特徵。在某些實施例中，化合物及組合物包含一或多種有效使化合物或組合物靶向細胞或組織之特徵。在某些實施例中，該等化合物及組合物相較於已公開揭示之化合物更強效、作用持續時間更長或治療價值更大。In some embodiments, the compounds and compositions comprise one or more features effective to increase potency. In some embodiments, the compounds and compositions comprise one or more features effective to increase tolerance. In some embodiments, the compounds and compositions comprise one or more features effective to target the compound or composition to cells or tissues. In some embodiments, the compounds and compositions are more potent, have a longer duration of action, or have greater therapeutic value than disclosed compounds.

相關申請案之交叉引用Cross-references to related applications

本申請案根據35 U.S.C. § 119(e)主張2023年6月20日提出申請之美國臨時申請案第63/509,259號之優先權權益，其視為本申請案之揭示內容之一部分且係以全文引用的方式併入本申請案之揭示內容中。This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63/509,259, filed on June 20, 2023, which is considered a part of the disclosure of this application and is incorporated by reference in its entirety into the disclosure of this application.

應理解，前述發明內容及以下實施方式均僅為例示性及解釋性的，而不限制所主張之實施例。本文所用之章節標題僅用於組織目的，而不應解釋為限制所描述之標的物。It should be understood that the foregoing invention content and the following embodiments are only exemplary and explanatory, and do not limit the claimed embodiments. The section headings used herein are only used for organizational purposes and should not be interpreted as limiting the subject matter described.

截至本申請案之申請日期，本申請案中引用之所有文件或文件部分，包括(但不限於)專利、專利申請案、文章、書籍、論文及GenBank、NCBI及其他序列參考記錄就本文所論述之文件部分以及全文在此係以引用方式明確地併入。As of the filing date of this application, all documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, theses, and GenBank, NCBI and other sequence reference records are expressly incorporated by reference for the part or portions of the documents discussed herein and in their entirety.

應理解，即使在上下文中與經修飾之化合物一起顯示，但本文所含之每一SEQ ID NO中所示之序列獨立於對糖部分、核苷間鍵聯或核鹼基之任何修飾。因此，由SEQ ID NO定義之化合物可獨立地包含對糖部分、核苷間鍵聯或核鹼基之一或多種修飾。由化合物編號或Ref ID NO提及之寡聚化合物指示核鹼基序列、化學修飾及模體之組合。It should be understood that the sequence shown in each SEQ ID NO contained herein is independent of any modification to the sugar moiety, the internucleoside linkage, or the nucleobase, even if shown in context with a modified compound. Thus, the compound defined by the SEQ ID NO may independently comprise one or more modifications to the sugar moiety, the internucleoside linkage, or the nucleobase. The oligomeric compounds referred to by the compound number or Ref ID NO indicate a combination of nucleobase sequences, chemical modifications, and motifs.

在本文中，除非另有明確說明，否則單數之使用包括複數。舉例而言，冠詞「一種/個(a及an)」在本文中用於指該冠詞之一個或一個以上(亦即指至少一個)文法受詞。舉例而言，「要素」意指一個要素或一個以上要素，例如複數個要素。除非另有說明，否則如本文所用，使用「或」意指「及/或」。此外，術語「包括(including)」以及諸如「包括(includes及included)」等其他形式之使用不為限制性的，且可與片語「包括(但不限於)」互換使用。定義As used herein, the use of the singular includes the plural unless expressly stated otherwise. For example, the articles "a" and "an" are used herein to refer to one or more than one (i.e., to at least one) of the grammatical objects of the article. For example, "an element" means one element or more than one element, for example, a plurality of elements. As used herein, the use of "or" means "and/or" unless otherwise stated. In addition, the use of the term "including" and other forms such as "includes and included" is not limiting and can be used interchangeably with the phrase "including, but not limited to."Definitions

除非另有指示，否則以下術語具有以下含義： 「富白胺酸重複激酶2」與術語「LRRK2」可互換使用，其係指LRRK2之任何核酸或蛋白質。LRRK2之例示性核苷酸及胺基酸序列可參見例如GenBank登錄號NM_198578.4 (以SEQ ID NO: 1併入本文中)，及NG_011709.2之核苷酸5002至149290 (以SEQ ID NO: 2併入本文中)。LRRK2序列之其他實例可經由可公開獲得之資料庫容易地獲得，例如GenBank、UniProt及OMIM。關於LRRK2之進一步資訊可參見例如www.ncbi.nlm.nih.gov/gene/?term=LRRK2。如本文所用，LRRK2亦指LRRK2基因之變化形式，包括SNP資料庫中所提供之變異體。已鑑別出LRRK2基因內之多種序列變化形式，且可參見例如NCBI dbSNP及UniProt (例如，參見www.ncbi.nlm.nih.gov/snp/?term=LRRK2)。「LRRK2 mRNA」意指編碼LRRK2蛋白之mRNA。LRRK2可按大寫或小寫來提及。Unless otherwise indicated, the following terms have the following meanings:"Leucine-rich repeat kinase 2" and the term "LRRK2" are used interchangeably to refer to any nucleic acid or protein of LRRK2. Exemplary nucleotide and amino acid sequences of LRRK2 can be found, for example, in GenBank accession number NM_198578.4 (incorporated herein as SEQ ID NO: 1), and nucleotides 5002 to 149290 of NG_011709.2 (incorporated herein as SEQ ID NO: 2). Other examples of LRRK2 sequences are readily available through publicly available databases, such as GenBank, UniProt, and OMIM. Further information about LRRK2 can be found, for example, at www.ncbi.nlm.nih.gov/gene/?term=LRRK2. As used herein, LRRK2 also refers to variants of the LRRK2 gene, including variants provided in the SNP database. A variety of sequence variants within the LRRK2 gene have been identified and can be found, for example, in NCBI dbSNP and UniProt (e.g., see www.ncbi.nlm.nih.gov/snp/?term=LRRK2). "LRRK2 mRNA" means mRNA encoding LRRK2 protein. LRRK2 can be referred to in uppercase or lowercase.

「LRRK2特異性抑制劑」係指能夠在分子層面上特異性地抑制LRRK2 RNA及/或LRRK2蛋白表現或活性之任何劑。舉例而言，LRRK2特異性抑制劑包括能夠抑制LRRK2 RNA及/或LRRK2蛋白之表現之核酸(包括寡核苷酸化合物)、肽、抗體、小分子及其他劑。"LRRK2 specific inhibitor" refers to any agent that can specifically inhibit the expression or activity of LRRK2 RNA and/or LRRK2 protein at the molecular level. For example, LRRK2 specific inhibitors include nucleic acids (including oligonucleotide compounds), peptides, antibodies, small molecules and other agents that can inhibit the expression of LRRK2 RNA and/or LRRK2 protein.

「2’-O-甲氧基乙基」或「2’-MOE」意指2’-O(CH₂)₂-OCH₃修飾。2’-O-甲氧基乙基修飾之糖係用2’-O(CH₂)₂-OCH₃代替核糖基環之2’-OH基團之經修飾糖。"2'-O-methoxyethyl" or "2'-MOE" means a 2'-O(CH₂ )₂ -OCH₃ modification. A 2'-O-methoxyethyl modified sugar is a sugar modified in which the 2'-OH group of the ribosyl ring is replaced with 2'-O(CH₂ )₂ -OCH₃ .

「5’起始位點」意指靶核酸或區域之與反義寡核苷酸之最3’核苷對齊之核苷酸。"5' start site" refers to the nucleotide of the target nucleic acid or region to which the 3'-most nucleoside of the antisense oligonucleotide is aligned.

「3’終止位點」意指與反義寡核苷酸之最5’核苷對齊之靶核酸或區域之核苷酸。"3' stop site" refers to the nucleotide of the target nucleic acid or region to which the 5'-most nucleoside of the antisense oligonucleotide is aligned.

「約」意指在一值之±10%內。舉例而言，若陳述「化合物達成約70%之LRRK2抑制」，則其暗示LRRK2水準受抑制之範圍為60%至80%。當約出現在一系列數值或範圍之前時，應理解，「約」可修飾該系列或範圍內之每一數值。"About" means within ±10% of a value. For example, if it is stated that "the compound achieves about 70% inhibition of LRRK2", it implies that the range of inhibition of LRRK2 levels is 60% to 80%. When about appears before a series of values or ranges, it should be understood that "about" can modify each value in the series or range.

「投與(administer或administering)」係指將本文所提供之化合物或組合物引入至個體以實現其預期功能之途徑。可使用之實例投與途徑包括(但不限於)鞘內(IT)投與、腦室內(ICV)投與、非經腸投與，諸如皮下投與、靜脈內投與、肌內投與、動脈內投與、腹膜內投與或顱內投與，例如鞘內或腦室內投與。"Administering" or "administering" refers to the route by which a compound or composition provided herein is introduced into a subject to achieve its intended function. Example routes of administration that may be used include, but are not limited to, intrathecal (IT), intracerebroventricular (ICV), parenteral administration, such as subcutaneous, intravenous, intramuscular, intraarterial, intraperitoneal, or intracranial, such as intrathecal or intracerebroventricular.

「改善」係指改進或減輕相關疾病、病症或疾患之至少一種指標、徵象或症狀。在某些實施例中，改善包括延遲或減緩疾患或疾病之一或多種指標之進展或嚴重程度。指標之進展或嚴重程度可藉由主觀或客觀量度來確定，其為熟習此項技術者所已知。"Improvement" refers to the improvement or alleviation of at least one indicator, sign or symptom of the relevant disease, disorder or condition. In certain embodiments, improvement includes delaying or slowing the progression or severity of one or more indicators of the disease or condition. The progression or severity of the indicators can be determined by subjective or objective measurement, which is known to those skilled in the art.

「動物」係指人類或非人類動物，包括(但不限於)小鼠、大鼠、兔、狗、貓、豬及非人類靈長類動物，包括(但不限於)猴及黑猩猩。“Animal” means human or non-human animals, including but not limited to mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including but not limited to monkeys and chimpanzees.

「反義寡核苷酸」或「反義股」意指包括與靶核酸(例如LRRK2 RNA或其區域)互補之區域的寡核苷酸。"Antisense oligonucleotide" or "antisense strand" means an oligonucleotide that includes a region complementary to a target nucleic acid (eg, LRRK2 RNA or a region thereof).

就寡核苷酸而言，「互補性」意指當兩個核鹼基序列以相反方向對齊時，此寡核苷酸或其一或多個區域之核鹼基序列與另一寡核苷酸或核酸或其一或多個區域之核鹼基序列互補。除非另有指定，否則如本文所闡述之互補核鹼基限於以下各對：腺嘌呤(A)與胸腺嘧啶(T)、腺嘌呤(A)與尿嘧啶(U)，及胞嘧啶(C)與鳥嘌呤(G)。互補寡核苷酸及/或核酸不需要在每一核苷處具有核鹼基互補性，且可包括一或多個核鹼基失配。相比之下，就寡核苷酸而言，「完全互補」或「100%互補」意指此等寡核苷酸在每一核苷處具有核鹼基匹配，而無任何核鹼基失配。With respect to oligonucleotides, "complementarity" means that the nucleobase sequence of one oligonucleotide or one or more regions thereof is complementary to the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof when the two nucleobase sequences are aligned in opposite directions. Unless otherwise specified, complementary nucleobases as described herein are limited to the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G). Complementary oligonucleotides and/or nucleic acids do not need to have nucleobase complementarity at every nucleoside and may include one or more nucleobase mismatches. In contrast, "fully complementary" or "100% complementary" with respect to oligonucleotides means that such oligonucleotides have nucleobase matches at every nucleoside without any nucleobase mismatches.

「組合物」或「醫藥組合物」意指適於投與給個體之物質混合物。舉例而言，組合物可包含一或多種化合物或其鹽及無菌水溶液。"Composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to an individual. For example, a composition may include one or more compounds or their salts and a sterile aqueous solution.

「共投與」意指以任何方式投與兩種或更多種化合物，其中兩者之藥理學效應在患者體內同時顯現。共投與不要求兩種化合物以單一醫藥組合物、以相同劑型、按相同投與途徑或同時投與。兩種化合物之效應不需要同時顯現。該等效應僅需要在一段時間內重疊，而無需同延。共投與包括同時或依序投與一或多種化合物。"Co-administration" means the administration of two or more compounds in any manner where the pharmacological effects of both compounds are manifested in the patient at the same time. Co-administration does not require that the two compounds be administered in a single pharmaceutical composition, in the same dosage form, by the same route of administration, or at the same time. The effects of the two compounds do not need to manifest at the same time. The effects need only overlap over a period of time, not be coextensive. Co-administration includes the administration of one or more compounds simultaneously or sequentially.

「結合基團」意指連接至寡核苷酸之原子團。結合基團視情況經由結合連接體連接至寡核苷酸。結合基團可例如改變併有該結合基團之化合物之分佈、靶向或半衰期。結合基團包括脂質(或親脂性部分)、配位體及其他靶向部分。"Binding group" means a group of atoms that is linked to an oligonucleotide. A binding group is optionally linked to an oligonucleotide via a binding linker. A binding group can, for example, alter the distribution, targeting, or half-life of a compound incorporating the binding group. Binding groups include lipids (or lipophilic moieties), ligands, and other targeting moieties.

「結合連接體」意指包含至少一個將連接部分連結至寡核苷酸之鍵的原子團。"Binding linker" means a group of atoms comprising at least one bond that links a linking moiety to an oligonucleotide.

就寡核苷酸而言，「一致性」意指此寡核苷酸或其一或多個區域之核鹼基序列與另一寡核苷酸或核酸或其一或多個區域之核鹼基序列匹配。寡核苷酸與另一寡核苷酸或核酸之一致性不要求每一核鹼基均匹配，且可包括一或多個不同的核鹼基。相比之下，就寡核苷酸而言，「完全一致」或「100%一致性」意指此等寡核苷酸在其長度上之每一相對位置具有與另一寡核苷酸或核酸相同之核鹼基。In the case of oligonucleotides, "identity" means that the nucleobase sequence of the oligonucleotide or one or more regions thereof matches the nucleobase sequence of another oligonucleotide or nucleic acid or one or more regions thereof. The identity of an oligonucleotide to another oligonucleotide or nucleic acid does not require that every nucleobase matches, and may include one or more different nucleobases. In contrast, in the case of oligonucleotides, "complete identity" or "100% identity" means that these oligonucleotides have the same nucleobase as another oligonucleotide or nucleic acid at every relative position along their length.

「個體」意指選擇進行治療或療法之人類或非人類動物。“Individual” means a human or non-human animal selected for treatment or therapy.

就靶核酸或蛋白質而言，「抑制表現或活性」意指相對於未經處理或對照樣品中之表現或活性，降低或阻斷此靶標之表現或活性，且不一定指示完全消除表現或活性。With respect to a target nucleic acid or protein, "inhibiting expression or activity" means reducing or blocking the expression or activity of this target relative to the expression or activity in an untreated or control sample, and does not necessarily indicate complete elimination of expression or activity.

如本文所用，術語「核苷間鍵聯」係寡核苷酸中毗鄰核苷之間的共價鍵聯。如本文所用，「經修飾之核苷間鍵聯」意指除磷酸二酯核苷間鍵聯以外之任何核苷間鍵聯。「硫代磷酸酯核苷間鍵聯」係經修飾之核苷間鍵聯，其中磷酸二酯核苷間鍵聯之一個非橋接氧原子經硫原子置換。As used herein, the term "internucleoside linkage" is a covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein, "modified internucleoside linkage" means any internucleoside linkage other than a phosphodiester internucleoside linkage. A "phosphorothioate internucleoside linkage" is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of the phosphodiester internucleoside linkage is replaced by a sulfur atom.

具有手性中心之代表性核苷間鍵聯包括(但不限於)烷基膦酸酯及硫代磷酸酯。如下文進一步闡述，可將包含具有手性中心之核苷間鍵聯的經修飾之寡核苷酸製備成包含立體隨機核苷間鍵聯的經修飾之寡核苷酸群體，或製備成包含呈特定立體化學構形之硫代磷酸酯鍵聯的經修飾之寡核苷酸群體。除非另有指示，否則本文所闡述之經修飾之寡核苷酸的手性核苷間鍵聯可為立構隨機的或呈特定立體化學構形。Representative internucleoside linkages with chiral centers include, but are not limited to, alkylphosphonates and phosphorothioates. As further described below, modified oligonucleotides comprising internucleoside linkages with chiral centers can be prepared as a population of modified oligonucleotides comprising stereorandom internucleoside linkages, or as a population of modified oligonucleotides comprising phosphorothioate linkages in a specific stereochemical configuration. Unless otherwise indicated, the chiral internucleoside linkages of the modified oligonucleotides described herein can be stereorandom or in a specific stereochemical configuration.

本揭示案之化合物亦可在構成此等化合物之一或多個原子處含有非天然比例之原子同位素。舉例而言，化合物可經放射性同位素放射標記，該等放射性同位素諸如為氚(³H)、碘-125 (¹²⁵I)或碳-14 (¹⁴C)。本揭示案化合物之所有同位素變化形式(無論是否具有放射性)均涵蓋在本揭示案之範圍內。The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (^3H ), iodine-125 (^125I ), or carbon-14 (^14C ). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

術語「同位素變異體」係指在構成治療劑(例如本文所揭示之化合物及/或經修飾之寡核苷酸)之一或多個原子處含有非天然比例之同位素的此一治療劑。在某些實施例中，治療劑之「同位素變異體」含有非天然比例之一或多種同位素，包括(但不限於)氫(H)、氘(²H)、氚(³H)、碳-11 (¹¹C)、碳-12 (¹²C)、碳-13 (¹³C)、碳-14 (¹⁴C)、氮-13 (¹³N)、氮-14 (¹⁴N)、氮-15 (¹⁵N)、氧-14 (¹⁴O)、氧-15 (¹⁵O)、氧-16 (¹⁶O)、氧-17 (¹⁷O)、氧-18 (¹⁸O)、氟-17 (¹⁷F)、氟-18 (¹⁸F)、磷-31 (³¹P)、磷-32 (³²P)、磷-33 (³³P)、硫-32 (³²S)、硫-33 (³³S)、硫-34 (³⁴S)、硫-35 (³⁵S)、硫-36 (³⁶S)、氯-35 (³⁵Cl)、氯-36 (³⁶Cl)、氯-37 (³⁷Cl)、溴-79 (⁷⁹Br)、溴-81 (⁸¹Br)、碘 123 (¹²³I)、碘-125 (¹²⁵I)、碘-127 (¹²⁷I)、碘-129 (¹²⁹I)及碘-131 (¹³¹I)。在某些實施例中，治療劑之「同位素變異體」含有非天然比例之一或多種同位素，包括(但不限於)氫(H)、氘(²H)、氚(³H)、碳-11 (¹¹C)、碳-12 (¹²C)、碳-13 (¹³C)、碳-14 (¹⁴C)、氮-13 (¹³N)、氮-14 (¹⁴N)、氮-15 (¹⁵N)、氧-14 (¹⁴O)、氧-15 (¹⁵O)、氧-16 (¹⁶O)、氧-17 (¹⁷O)、氧-18 (¹⁸O)、氟-17 (¹⁷F)、氟-18 (¹⁸F)、磷-31 (³¹P)、磷-32 (³²P)、磷-33 (³³P)、硫-32 (³²S)、硫-33 (³³S)、硫-34 (³⁴S)、硫-35 (³⁵S)、硫-36 (³⁶S)、氯-35 (³⁵Cl)、氯-36 (³⁶Cl)、氯-37 (³⁷Cl)、溴-79 (⁷⁹Br)、溴-81 (⁸¹Br)、碘 123 (¹²³I)、碘-125 (¹²⁵I)、碘-127 (¹²⁷I)、碘-129 (¹²⁹I)及碘-131 (¹³¹I)。The term "isotopic variant" refers to a therapeutic agent (eg, a compound and/or modified oligonucleotide disclosed herein) that contains unnatural proportions of isotopes at one or more atoms that constitute such an agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes including, but not limited to, hydrogen (H), deuterium (^2H ), tritium (^3H ), carbon-11 (^11C ), carbon-12 (^12C ), carbon-13 (^13C ), carbon-14 (^14C ), nitrogen-13 (^13N ), nitrogen-14 (^14N ), nitrogen-15 (^15N ), oxygen-14 (^14O ), oxygen-15 (^15O ), oxygen-16 (^16O ), oxygen-17 (^17O ), oxygen-18 (^18O ), fluorine-17 (^17F ), fluorine-18 (^18F ), phosphorus-31 (^31P ), phosphorus-32 (^32P ), phosphorus-33 (^33P ), sulfur-32 (³² S), sulfur-33 (³³ S), sulfur-34 (³⁴ S), sulfur-35 (³⁵ S), sulfur-36 (³⁶ S), chlorine-35 (³⁵ Cl), chlorine-36 (³⁶ Cl), chlorine-37 (³⁷ Cl), bromine-79 (⁷⁹ Br), bromine-81 (⁸¹ Br), iodine-123 (¹²³ I), iodine-125 (¹²⁵ I), iodine-127 (¹²⁷ I), iodine-129 (¹²⁹ I) and iodine-131 (¹³¹ I). In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes including, but not limited to, hydrogen (H), deuterium (^2H ), tritium (^3H ), carbon-11 (^11C ), carbon-12 (^12C ), carbon-13 (^13C ), carbon-14 (^14C ), nitrogen-13 (^13N ), nitrogen-14 (^14N ), nitrogen-15 (^15N ), oxygen-14 (^14O ), oxygen-15 (^15O ), oxygen-16 (^16O ), oxygen-17 (^17O ), oxygen-18 (^18O ), fluorine-17 (^17F ), fluorine-18 (^18F ), phosphorus-31 (^31P ), phosphorus-32 (^32P ), phosphorus-33 (^33P ), sulfur-32 (³² S), sulfur-33 (³³ S), sulfur-34 (³⁴ S), sulfur-35 (³⁵ S), sulfur-36 (³⁶ S), chlorine-35 (³⁵ Cl), chlorine-36 (³⁶ Cl), chlorine-37 (³⁷ Cl), bromine-79 (⁷⁹ Br), bromine-81 (⁸¹ Br), iodine-123 (¹²³ I), iodine-125 (¹²⁵ I), iodine-127 (¹²⁷ I), iodine-129 (¹²⁹ I) and iodine-131 (¹³¹ I).

將理解，在治療劑(例如本文所揭示之化合物及/或經修飾之寡核苷酸)中，根據熟習此項技術者之判斷，在可行之情形下，任何氫可為例如²H，或任何碳可為例如¹³C，或任何氮可為例如¹⁵N，或任何氧可為例如¹⁸O。在某些實施例中，治療劑之「同位素變異體」含有非天然比例之氘(D)。It will be understood that in a therapeutic agent (e.g., a compound and/or modified oligonucleotide disclosed herein), where applicable, any hydrogen may be, for example,² H, or any carbon may be, for example,¹³ C, or any nitrogen may be, for example,¹⁵ N, or any oxygen may be, for example,¹⁸ O, according to the judgment of one skilled in the art. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of deuterium (D).

「脂質」或「親脂性部分」係指脂肪族、環狀(諸如脂環族)或多環(諸如多脂環族)化合物，諸如類固醇(例如固醇)或直鏈或具支鏈脂肪族烴。術語脂質包括膽固醇、視黃酸、膽酸、金剛烷乙酸、1-芘丁酸、二氫睪固酮、1,3-雙-O(十六烷基)甘油、香葉草基氧己醇(geranyloxyhexyanol)、十六烷基甘油、冰片、薄荷醇、1,3-丙二醇、十七烷基、棕櫚酸、肉豆蔻酸、O3-(油醯基)石膽酸、O3-(油醯基)膽烯酸、布洛芬(ibuprofen)、萘普生(naproxen)、二甲氧基三苯甲基或吩噁嗪。術語脂質包括飽和或不飽和C₄-C₃₀烴鏈(例如C₄-C₃₀烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₅-C₂₀烴鏈(例如直鏈C₅-C₂₀烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₁₄-C₂₀烴鏈(例如直鏈C₁₄-C₂₀烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₆-C₁₈烴鏈(例如直鏈C₆-C₁₈烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₁₆烴鏈(例如直鏈C₁₆烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₁₇烴鏈(例如直鏈C₁₇烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₁₈烴鏈(例如直鏈C₁₈烷基或烯基)。在某些實施例中，親脂性部分含有飽和或不飽和C₂₂烴鏈(例如直鏈C₂₂烷基或烯基)。"Lipid" or "lipophilic moiety" refers to an aliphatic, cyclic (eg, alicyclic) or polycyclic (eg, polyalicyclic) compound, such as a steroid (eg, sterol) or a straight or branched chain aliphatic hydrocarbon. The term lipid includes cholesterol, retinoic acid, bile acid, adamantaneacetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O (hexadecyl) glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propylene glycol, heptadecyl, palmitic acid, myristic acid, O3-(oleyl) cholecalciferol, O3-(oleyl) cholecalciferol, ibuprofen, naproxen, dimethoxytrityl or phenoxazine. The term lipid includes saturated or unsaturated C₄ -C₃₀ alkyl chains (e.g., C₄ -C₃₀ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C₅ -C₂₀ hydrocarbon chain (e.g., a straight chain C₅ -C₂₀ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chain (e.g., a straight chain C₁₄ -C₂₀ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C₆ -C₁₈ hydrocarbon chain (e.g., a straight chain C₆ -C₁₈ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated C₁₆ hydrocarbon chain (e.g., a straight chain C₁₆ alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated_C17 hydrocarbon chain (e.g., a straight chain_C17 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated_C18 hydrocarbon chain (e.g., a straight chain_C18 alkyl or alkenyl). In certain embodiments, the lipophilic moiety contains a saturated or unsaturated_C22 hydrocarbon chain (e.g., a straight chain_C22 alkyl or alkenyl).

「失配」或「非互補」意指當將第一寡核苷酸/核酸與第二寡核苷酸/核酸以反平行定向對齊時，第一寡核苷酸或核酸之核鹼基不與第二寡核苷酸或核酸之相應核鹼基互補。舉例而言，核鹼基、包括(但不限於)通用核鹼基、肌苷及次黃嘌呤，能夠與至少一個核鹼基雜交，但仍與其所雜交之核鹼基失配或不互補。作為另一實例，當將第一與第二寡核苷酸以反平行定向對齊時，第一寡核苷酸/核酸中不能與第二寡核苷酸/核酸之相應核鹼基雜交之核鹼基為失配或非互補核鹼基。"Mismatched" or "non-complementary" means that a nucleobase of the first oligonucleotide or nucleic acid is not complementary to the corresponding nucleobase of the second oligonucleotide or nucleic acid when the first oligonucleotide/nucleic acid is aligned in an antiparallel orientation with the second oligonucleotide/nucleic acid. For example, nucleobases, including but not limited to the universal nucleobases, inosine and hypoxanthine, are capable of hybridizing with at least one nucleobase but are still mismatched or non-complementary to the nucleobase to which it hybridizes. As another example, a nucleobase in the first oligonucleotide/nucleic acid that is unable to hybridize with the corresponding nucleobase of the second oligonucleotide/nucleic acid when the first and second oligonucleotides are aligned in an antiparallel orientation is a mismatched or non-complementary nucleobase.

「經修飾之寡核苷酸」意指其中至少一個糖、核鹼基或核苷間鍵聯經修飾之寡核苷酸。"Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase or internucleoside linkage has been modified.

「調節」係指改變或調整細胞、組織、器官或生物體中之特徵。舉例而言，調節LRRK2 RNA可意指增加或減少細胞、組織、器官或生物體中LRRK2 RNA及/或LRRK2蛋白之水準。「調節劑」引起細胞、組織、器官或生物體中之變化。舉例而言，LRRK2化合物可為減少細胞、組織、器官或生物體中LRRK2 RNA及/或LRRK2蛋白之量的調節劑。"Modulate" means to change or adjust a characteristic in a cell, tissue, organ, or organism. For example, modulating LRRK2 RNA may mean increasing or decreasing the level of LRRK2 RNA and/or LRRK2 protein in a cell, tissue, organ, or organism. A "modulator" causes a change in a cell, tissue, organ, or organism. For example, a LRRK2 compound may be a modulator that decreases the amount of LRRK2 RNA and/or LRRK2 protein in a cell, tissue, organ, or organism.

「模體」意指寡核苷酸中未經修飾及經修飾之糖部分、核鹼基及/或核苷間鍵聯之模式。"Motif" refers to the pattern of unmodified and modified sugar moieties, nucleobases and/or internucleoside linkages in an oligonucleotide.

「核酸」係指由單體核苷酸構成之分子。核酸包括(但不限於)核糖核酸(RNA)、去氧核糖核酸(DNA)、單股核酸及雙股核酸。"Nucleic acid" refers to a molecule composed of monomeric nucleotides. Nucleic acids include (but are not limited to) ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acid and double-stranded nucleic acid.

「核鹼基」意指能夠與另一核酸之鹼基配對之雜環部分。如本文所用，「天然核鹼基」為腺嘌呤(A)、胸腺嘧啶(T)、胞嘧啶(C)、尿嘧啶(U)及鳥嘌呤(G)。「經修飾之核鹼基」係經化學修飾之天然核鹼基。「通用鹼基」或「通用核鹼基」係除天然核鹼基及經修飾之核鹼基以外且能夠與任何核鹼基配對之核鹼基。"Nucleobase" means a heterocyclic moiety that is capable of pairing with a base of another nucleic acid. As used herein, "natural nucleobases" are adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). "Modified nucleobases" are natural nucleobases that have been chemically modified. "Universal base" or "universal nucleobase" is a nucleobase other than natural nucleobases and modified nucleobases that is capable of pairing with any nucleobase.

「核鹼基序列」意指核酸或寡核苷酸中鄰接核鹼基之順序，該順序與任何糖或核苷間鍵聯無關。"Nucleobase sequence" means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.

「核苷」意指包含核鹼基及糖部分之化合物。核鹼基及糖部分各自獨立地未經修飾或經修飾。「經修飾之核苷」意指包含經修飾之核鹼基及/或經修飾之糖部分的核苷。經修飾之核苷包括缺少核鹼基之無鹼基核苷。"Nucleoside" means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each independently unmodified or modified. "Modified nucleoside" means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides lacking a nucleobase.

「寡聚化合物」意指包含一或多種寡核苷酸及視情況一或多種額外特徵(諸如結合基團或末端基團)之化合物。寡聚化合物之實例包括單股及雙股化合物，諸如寡核苷酸、反義寡核苷酸、干擾RNA化合物(RNAi化合物)、靶向微小RNA之寡核苷酸、基於佔位之化合物(例如mRNA加工或轉譯阻斷化合物及剪接化合物)。RNAi化合物包括雙股化合物(例如短干擾RNA (siRNA)及雙股RNA (dsRNA))及單股化合物(例如單股siRNA (ssRNA)、單股RNAi (ssRNAi)、短髮夾RNA (shRNA)及微小RNA模擬物)，其至少部分地經由RNA誘導之沈默複合物(RISC)路徑起作用，從而經由稱為RNA干擾(RNAi)之過程導致靶核酸之序列特異性降解及/或螯合。術語「RNAi化合物」意欲等同於用於描述能夠介導序列特異性RNA干擾之核酸化合物之其他術語，例如干擾RNA (iRNA)、iRNA劑、RNAi劑、短干擾寡核苷酸、短干擾核酸、短干擾經修飾寡核苷酸、經化學修飾之siRNA等。另外，術語「RNAi」意欲等同於用於描述序列特異性RNA干擾之其他術語。"Oligomeric compound" means a compound comprising one or more oligonucleotides and, optionally, one or more additional features, such as binding groups or terminal groups. Examples of oligomeric compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), oligonucleotides targeting microRNAs, occupancy-based compounds such as mRNA processing or translation blocking compounds and splicing compounds. RNAi compounds include double-stranded compounds (e.g., short interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics) that act at least in part through the RNA-induced silencing complex (RISC) pathway, thereby causing sequence-specific degradation and/or sequestration of target nucleic acids through a process known as RNA interference (RNAi). The term "RNAi compound" is intended to be equivalent to other terms used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agent, RNAi agent, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, etc. Additionally, the term "RNAi" is intended to be equivalent to other terms used to describe sequence-specific RNA interference.

「寡聚雙鏈體」意指由兩種具有互補核鹼基序列之寡聚化合物形成的雙鏈體。寡聚雙鏈體之每一寡聚化合物可稱為「雙鏈體化之寡聚化合物」。寡聚雙鏈體之每一寡聚化合物之寡核苷酸可包括非互補懸垂核苷。在一些實施例中，術語「雙鏈體化之寡聚化合物」及「經修飾之寡核苷酸」可互換使用。在其他實施例中，術語「寡聚雙鏈體」與「化合物」可互換使用。"Oligoduplex" means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of the oligomeric duplex may be referred to as a "duplexed oligomeric compound". The oligonucleotides of each oligomeric compound of the oligomeric duplex may include non-complementary pendant nucleosides. In some embodiments, the terms "duplexed oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligoduplex" and "compound" are used interchangeably.

「寡核苷酸」意指連接核苷之聚合物，每一核苷可彼此獨立地經修飾或未經修飾。"Oligonucleotide" refers to a polymer of linked nucleosides, each of which may be independently modified or unmodified.

「非經腸投與」意指經由注射或輸注投與。非經腸投與包括皮下投與、靜脈內投與、肌內投與、動脈內投與、腹膜內投與或顱內投與，例如鞘內或腦室內投與。"Parenteral administration" means administration by injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, such as intrathecal or intraventricular administration.

「醫藥學上可接受之載劑或稀釋劑」意指適用於投與給個體之任何物質。在某些實施例中，醫藥學上可接受之載劑或稀釋劑有助於將化合物投與給個體並由個體吸收，且可包括在本揭示案之組合物中，而不會對患者產生顯著不良毒性效應。醫藥學上可接受之賦形劑之非限制性實例包括水、NaCl、生理鹽水溶液及諸如此類。舉例而言，醫藥學上可接受之載劑可為無菌水溶液，諸如PBS或注射用水。熟習此項技術者將認識到，其他醫藥賦形劑可用於本揭示案中。"Pharmaceutically acceptable carrier or diluent" means any substance suitable for administration to an individual. In certain embodiments, a pharmaceutically acceptable carrier or diluent facilitates administration of the compound to an individual and absorption by the individual and may be included in the compositions of the present disclosure without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solutions, and the like. For example, a pharmaceutically acceptable carrier may be a sterile aqueous solution, such as PBS or water for injection. Those skilled in the art will recognize that other pharmaceutical excipients may be used in the present disclosure.

「醫藥學上可接受之鹽」意指或係指化合物(諸如寡聚化合物或寡核苷酸)之生理學及醫藥學上可接受之鹽，亦即保留母體化合物之期望生物活性且不會產生不期望之毒性效應之鹽。"Pharmaceutically acceptable salt" means or refers to a physiologically and pharmaceutically acceptable salt of a compound (such as an oligomeric compound or oligonucleotide), that is, a salt that retains the desired biological activity of the parent compound and does not produce undesired toxicological effects.

在本文中可互換使用之「原肌凝蛋白受體激酶B」或「TrkB」意指腦源性神經營養因子(BDNF)蛋白受體，其由NTRK2基因編碼。TrkB亦稱為酪胺酸受體激酶B、BDNF/NT-3生長因子受體及2型神經營養酪胺酸激酶受體。"Tropomyosin receptor kinase B" or "TrkB", used interchangeably herein, refers to the brain-derived neurotrophic factor (BDNF) protein receptor, which is encoded by the NTRK2 gene. TrkB is also known as tyrosine receptor kinase B, BDNF/NT-3 growth factor receptor, and neurotrophic tyrosine kinase receptor type 2.

如本文所用，醫藥學上可接受之鹽係保留本文所提供化合物之生物性質且無毒或不會在其他方面為醫藥用途不期望之任何鹽。本文所揭示治療劑之醫藥學上可接受之鹽包括利用相對無毒酸或鹼製備之鹽，此取決於在本文所闡述化合物或經修飾之寡核苷酸上所發現之特定取代基。As used herein, a pharmaceutically acceptable salt is any salt that retains the biological properties of the compounds provided herein and is not toxic or otherwise undesirable for pharmaceutical uses. Pharmaceutically acceptable salts of the therapeutic agents disclosed herein include salts prepared using relatively nontoxic acids or bases, depending on the particular substituents found on the compounds or modified oligonucleotides described herein.

當本揭示案之化合物含有相對酸性官能基時，可藉由使此等化合物之中性形式與足夠量之純淨或於適宜惰性溶劑中之期望鹼接觸來獲得鹼加成鹽。When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired base either neat or in a suitable inert solvent.

當本揭示案之化合物含有相對鹼性官能基時，可藉由使此等化合物之中性形式與足夠量之純淨或於適宜惰性溶劑中之期望酸接觸來獲得酸加成鹽。When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid either neat or in a suitable inert solvent.

因此，本揭示案之化合物可以鹽形式存在，諸如與醫藥學上可接受之酸的鹽。此等鹽可源自此項技術中所熟知之多種有機及無機相對離子。此等鹽包括(但不限於)：(1)與有機或無機酸形成之酸加成鹽，該等有機或無機酸諸如為鹽酸、氫溴酸、硫酸、硝酸、磷酸、胺基磺酸、乙酸、三氟乙酸、三氯乙酸、丙酸、己酸、環戊基丙酸、羥乙酸、戊二酸、丙酮酸、乳酸、丙二酸、琥珀酸、山梨酸、抗壞血酸、蘋果酸、馬來酸、富馬酸、酒石酸、檸檬酸、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、苦味酸、肉桂酸、扁桃酸、酞酸、月桂酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羥基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟腦酸、樟腦磺酸、4-甲基雙環[2.2.2]-辛-2-烯-1-甲酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、第三丁基乙酸、月桂基硫酸、葡萄糖酸、苯甲酸、麩胺酸、羥基萘酸、柳酸、硬脂酸、環己基胺基磺酸、奎尼酸、黏康酸及類似酸；或(2)當存在於母體化合物中之酸性質子(a)經金屬離子(例如鹼金屬離子、鹼土離子或鋁離子)或鹼金屬或鹼土金屬氫氧化物(諸如氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂、氫氧化鋁、氫氧化鋰、氫氧化鋅及氫氧化鋇)、氨置換或(b)與有機鹼(諸如脂肪族、脂環族或芳香族有機胺，諸如氨、甲胺、二甲胺、二乙胺、甲吡啶、乙醇胺、二乙醇胺、三乙醇胺、乙二胺、離胺酸、精胺酸、鳥胺酸、膽鹼、N,N'-二苯甲基乙二胺、氯普魯卡因(chloroprocaine)、二乙醇胺、普魯卡因、N-苯甲基苯乙胺、N-甲基葡萄糖胺六氫吡嗪、參(羥甲基)-胺基甲烷、四甲基氫氧化銨及諸如此類)配位時形成之鹽(例如，參見Berge等人，「Pharmaceutical Salts」, Journal of Pharmaceutical Science, 1977, 66, 1-19)。Thus, the compounds of the present disclosure may exist in the form of salts, such as salts with pharmaceutically acceptable acids. Such salts may be derived from a variety of organic and inorganic counterions known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, aminosulfonic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, hydroxyacetic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, apple acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid; , cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamine, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylaminosulfonic acid , quinic acid, muconic acid and similar acids; or (2) when the acidic protons present in the parent compound are replaced (a) by metal ions (e.g., alkali metal ions, alkali earth ions or aluminum ions) or alkali metal or alkali earth metal hydroxides (such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide and barium hydroxide), ammonia or (b) by organic bases (such as aliphatic, alicyclic or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picolinyl Salts formed when the amine is coordinated with 2-hydroxy-1-nitropropene (e.g., 1-hydroxy-2-nitropropene), 1-hydroxy-1-nitropropene (e.g., 1-hydroxy-1 ...

醫藥學上可接受之鹽進一步包括(僅舉例而言而不限於)鈉、鉀、鈣、鎂、銨、四烷基銨及諸如此類，及(當化合物含有鹼性官能基時)無毒有機或無機酸之鹽，諸如氫鹵化物(例如鹽酸鹽及氫溴酸鹽)、硫酸鹽、磷酸鹽、胺基磺酸鹽、硝酸鹽、乙酸鹽、三氟乙酸鹽、三氯乙酸鹽、丙酸鹽、己酸鹽、環戊基丙酸鹽、羥乙酸鹽、戊二酸鹽、丙酮酸鹽、乳酸鹽、丙二酸鹽、琥珀酸鹽、山梨酸鹽、抗壞血酸鹽、蘋果酸鹽、馬來酸鹽、富馬酸鹽、酒石酸鹽、檸檬酸鹽、苯甲酸鹽、3-(4-羥基苯甲醯基)苯甲酸鹽、苦味酸鹽、肉桂酸鹽、扁桃酸鹽、酞酸鹽、月桂酸鹽、甲磺酸鹽(methanesulfonate、mesylate)、乙磺酸鹽、1,2-乙二磺酸鹽、2-羥基乙磺酸鹽、苯磺酸鹽(benzenesulfonate、besylate)、4-氯苯磺酸鹽、2-萘磺酸鹽、4-甲苯磺酸鹽、樟腦酸鹽、樟腦磺酸鹽、4-甲基雙環[2.2.2]-辛-2-烯-1-甲酸鹽、葡庚糖酸鹽、3-苯基丙酸鹽、三甲基乙酸鹽、第三丁基乙酸鹽、月桂基硫酸鹽、葡萄糖酸鹽、苯甲酸鹽、麩胺酸鹽、羥基萘酸鹽、柳酸鹽、硬脂酸鹽、環己基胺基磺酸鹽、奎尼酸鹽、黏康酸鹽及諸如此類。在一些實施例中，本文所揭示之化合物及經修飾之寡核苷酸的醫藥學上可接受之鹽為鈉鹽或鉀鹽。在一些實施例中，本文所揭示之化合物及經修飾之寡核苷酸的醫藥學上可接受之鹽為鈉鹽。Pharmaceutically acceptable salts further include, by way of example and not limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and (when the compound contains a basic functional group) salts of non-toxic organic or inorganic acids such as hydrohalides (e.g., hydrochlorides and hydrobromides), sulfates, phosphates, sulfamate, nitrates, acetates, trifluoroacetates, trichloroacetic acid. Salt, propionate, caproate, cyclopentylpropionate, hydroxyacetate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, apple acid salt, maleate, fumarate, tartaric acid salt, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate , laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, Camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamine, hydroxynaphthoate, salicylate, stearate, cyclohexylaminesulfonate, quinate, muconate, and the like. In some embodiments, the pharmaceutically acceptable salt of the compounds and modified oligonucleotides disclosed herein is a sodium salt or a potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compounds and modified oligonucleotides disclosed herein is a sodium salt.

化合物之中性形式較佳藉由使鹽與鹼或酸接觸且以習用方式分離母體化合物來再生。化合物之母體形式可在某些物理性質(諸如於極性溶劑中之溶解性)方面與各種鹽形式不同。在實施例中，本揭示案之化合物含有容許將該等化合物轉化成鹼加成鹽或酸加成鹽之鹼性及酸性官能基二者。化合物之中性形式可藉由使鹽與鹼或酸接觸且以習用方式分離母體化合物來再生。化合物之母體形式在某些物理性質(諸如於極性溶劑中之溶解性)方面與各種鹽形式不同，但除非明確指示，否則出於本揭示案之目的，本文所揭示之鹽等效於化合物之母體形式。The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, the compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into base addition salts or acid addition salts. The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but unless expressly indicated, the salts disclosed herein are equivalent to the parent forms of the compound for purposes of the present disclosure.

「醫藥劑」意指在投與給個體時提供治療益處之化合物。"Pharmaceutical agent" means a compound that provides a therapeutic benefit when administered to a subject.

「硫代磷酸酯鍵聯」意指經修飾之磷酸酯鍵聯，其中一個非橋接氧原子經硫原子置換。"Phosphorothioate linkage" means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced by a sulfur atom.

「部分」意指核酸中確定數量之鄰接(亦即連接)核鹼基。在某些實施例中，部分係靶核酸中確定數量之鄰接核鹼基。在某些實施例中，部分係寡核苷酸中確定數量之鄰接核鹼基。"Portion" means a defined number of adjacent (i.e., linked) nucleobases in a nucleic acid. In certain embodiments, a portion is a defined number of adjacent nucleobases in a target nucleic acid. In certain embodiments, a portion is a defined number of adjacent nucleobases in an oligonucleotide.

「預防」係指在一段時間內延遲或預先阻止疾病、病症或疾患之發作、發展或進展。"Prevention" means delaying or arresting for a period of time the onset, development or progression of a disease, symptom or condition.

「RNA干擾化合物」或「RNAi化合物」意指至少部分地經由RNA誘導之沈默複合物(RISC)路徑或Ago2、而不經由RNA酶H起作用，以調節靶核酸及/或由靶核酸編碼之蛋白質之化合物。RNAi化合物包括(但不限於)雙股siRNA、單股siRNA及微小RNA，包括微小RNA模擬物。"RNA interference compound" or "RNAi compound" means a compound that acts at least in part through the RNA-induced silencing complex (RISC) pathway or Ago2, rather than through RNase H, to regulate a target nucleic acid and/or a protein encoded by the target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNA, including microRNA mimetics.

「有義寡核苷酸」或「有義股」意指雙股化合物之股，其包括與該化合物之反義股區域實質上互補之區域。"Sense oligonucleotide" or "sense strand" means a strand of a two-stranded compound that includes a region that is substantially complementary to the antisense strand of the compound.

就靶核酸或蛋白質而言，「特異性地抑制」意指降低或阻斷靶核酸或蛋白質之表現或活性，同時最小化或消除對非靶核酸或蛋白質之效應。With respect to a target nucleic acid or protein, "specifically inhibiting" means reducing or blocking the expression or activity of the target nucleic acid or protein while minimizing or eliminating the effects on non-target nucleic acids or proteins.

就寡核苷酸而言，「亞單元」意指如本文所提供之核苷酸、核苷、核鹼基或糖或者經修飾之核苷酸、核苷、核鹼基或糖。With respect to an oligonucleotide, "subunit" means a nucleotide, nucleoside, nucleobase or sugar, or a modified nucleotide, nucleoside, nucleobase or sugar as provided herein.

「靶核酸」、「靶RNA」及「核酸靶標」均意指能夠由本文所闡述之化合物靶向之核酸。"Target nucleic acid," "target RNA," and "nucleic acid target" all refer to a nucleic acid that can be targeted by the compounds described herein.

「靶區域」意指一或多種化合物靶向之靶核酸之一部分。"Target region" means a portion of a target nucleic acid to which one or more compounds are targeted.

「靶向部分」意指例如與不存在此一部分之化合物相比，對選定靶標(例如分子、細胞或細胞類型、區室(例如細胞或器官區室)、組織、器官或身體區域)提供增強親和力之結合基團。"Targeting moiety" means a binding group that provides enhanced affinity for a selected target (e.g., a molecule, cell or cell type, compartment (e.g., a cellular or organ compartment), tissue, organ, or body region), e.g., compared to a compound without such moiety.

「末端基團」意指共價連接至寡核苷酸末端之化學基團或原子團。"Terminus group" refers to a chemical group or group of atoms covalently linked to the end of an oligonucleotide.

「治療有效量」或「有效量」意指化合物、醫藥劑或組合物為個體提供治療益處之量。「治療有效量」或「有效量」係相對於不存在化合物時，化合物足以實現所述目的之量(例如，達成投與該化合物之效應，治療、預防或改善疾病，或減少疾病或疾患之一或多種症狀)。「治療有效量」或「有效量」之實例為足以有助於治療、預防、改善或減少疾病之一或多種症狀之量。一或多種症狀之「減少」(及此片語之文法等效形式)意指降低該(等)症狀之嚴重程度或頻率，或消除該(等)症狀。藥物之「預防有效量」係當投與給個體時將具有預期預防效應之藥物量，例如預防或延遲損傷、疾病、病狀或疾患之發作(或復發)，或降低損傷、疾病、病狀或疾患或其症狀發作(或復發)之可能性。如本文所用，術語「治療有效量」係指治療劑足以為個體提供治療益處之量，諸如如上文所闡述治療、預防或改善疾病或病症或其症狀。舉例而言，對於給定參數，治療有效量將顯示出至少5%、10%、15%、20%、25%、40%、50%、60%、75%、80%、90%或至少100%之增加或減少。治療功效亦可表述為「倍」數增加或減小。舉例而言，治療有效量之效應可為對照的至少1.2倍、1.5倍、2倍、5倍或更高。"Therapeutically effective amount" or "effective amount" means the amount of a compound, pharmaceutical agent, or composition that provides a therapeutic benefit to an individual. "Therapeutically effective amount" or "effective amount" is an amount of a compound sufficient to achieve the stated purpose (e.g., to achieve the effect of administration of the compound, to treat, prevent, or ameliorate a disease, or to reduce one or more symptoms of a disease or disorder) relative to the absence of the compound. Examples of "therapeutically effective amount" or "effective amount" are amounts sufficient to help treat, prevent, ameliorate, or reduce one or more symptoms of a disease. "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptom(s), or eliminating the symptom(s). A "prophylactically effective amount" of a drug is an amount of the drug that, when administered to an individual, will have the desired prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, condition, or illness, or reducing the likelihood of the onset (or recurrence) of an injury, disease, condition, or illness, or a symptom thereof. As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to provide a therapeutic benefit to an individual, such as treating, preventing, or ameliorating a disease or disorder, or a symptom thereof, as described above. For example, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100% for a given parameter. The therapeutic efficacy can also be expressed as a "fold" increase or decrease. For example, the effect of a therapeutically effective amount can be at least 1.2 times, 1.5 times, 2 times, 5 times or more of the control.

術語「治療(treating或treatment)」係指在療法或改善損傷、疾病、病狀或疾患方面之任何成功跡象，包括任何客觀或主觀參數，諸如減輕；緩解；減少症狀或使患者更能耐受損傷、病狀或疾患；減緩退化或衰退之速率；使退化終點較少地減弱；改進患者之身體或心理健康。症狀之治療或改善可基於客觀或主觀參數，包括身體檢查結果。術語「治療」及其詞形變化可包括預防損傷、病狀、疾患或疾病。在實施例中，治療為預防。在實施例中，治療不包括預防。The term "treating" or "treatment" refers to any sign of success in curing or ameliorating an injury, disease, ailment, or illness, including any objective or subjective parameter, such as amelioration; relief; reduction of symptoms or making the patient more tolerant of the injury, disease, or illness; slowing the rate of degeneration or decline; making the endpoint of degeneration less severe; improving the patient's physical or psychological well-being. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including physical examination results. The term "treating" and its variations may include preventing an injury, disease, ailment, or illness. In embodiments, treatment is prevention. In embodiments, treatment does not include prevention.

如本文所用(且如此項技術中所充分理解)，「治療(treating或treatment)」亦廣泛地包括針對個體疾患獲得有益或期望結果(包括臨床結果)之方法。有益或期望之臨床結果可包括(但不限於)緩和或改善一或多種症狀或疾患、減輕疾病程度、使疾病狀態穩定(亦即不惡化)、預防疾病傳播或擴散、延遲或減緩疾病進展、改善或減輕疾病狀態、減少疾病復發，以及緩解，無論為部分還是全部，且無論可偵測到還是偵測不到。換言之，如本文所用之「治療」包括疾病之任何治癒、改善或預防。治療可預防疾病發生；抑制疾病傳播；減輕疾病症狀；完全或部分消除疾病潛在原因；縮短疾病持續時間；或該等事項之組合。As used herein (and as is well understood in the art), "treating" or "treatment" also broadly includes methods for obtaining beneficial or desired results (including clinical results) for an individual disease. Beneficial or desired clinical results may include (but are not limited to) alleviation or improvement of one or more symptoms or diseases, reduction in the severity of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease transmission or spread, delay or slowing of disease progression, improvement or reduction of the disease state, reduction of disease recurrence, and remission, whether partial or complete, and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, improvement, or prevention of disease. Treatment may prevent the disease from occurring; inhibit its spread; reduce the symptoms of the disease; completely or partially eliminate the underlying cause of the disease; shorten the duration of the disease; or a combination of these things.

如本文所用，「治療(treating及treatment)」包括預防性治療。治療方法包括向個體投與治療有效量之本文所闡述之化合物。投與步驟可由單次投與組成，或可包括一系列投與。治療期之長度取決於多種因素，諸如疾患之嚴重程度、患者年齡、化合物濃度、治療中所用組合物之活性或其組合。亦應瞭解，用於治療或預防之劑的有效劑量可在特定治療或預防方案之過程中增加或減少。在一些情況下，可能需要長期投與。舉例而言，將組合物以足以治療患者之量及持續時間向個體投與。「治療」係指向動物投與化合物或醫藥組合物，以實現動物疾病、病症或疾患之改變或改進。As used herein, "treating" and "treatment" include preventive treatment. The treatment method includes administering to an individual a therapeutically effective amount of a compound as described herein. The administration step may consist of a single administration, or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may increase or decrease during the course of a specific treatment or prevention regimen. In some cases, long-term administration may be required. For example, the composition is administered to an individual in an amount and for a duration sufficient to treat the patient. "Treatment" refers to the administration of a compound or pharmaceutical composition to an animal to effect a change or improvement in a disease, disorder or condition in the animal.

本揭示案之某些化合物具有不對稱碳原子(光學或手性中心)或雙鍵；鏡像異構物、外消旋物、非鏡像異構物、互變異構物、幾何異構物、就絕對立體化學而言可定義為(R)-或(S)-或對於胺基酸而言可定義為(D)-或(L)-之立體異構形式以及個別異構物涵蓋在本揭示案之範圍內。本揭示案之化合物不包括此項技術中已知之太不穩定而不能合成及/或分離之彼等化合物。本揭示案意欲包括呈外消旋及光學純形式之化合物。光學活性(R)-及(S)-或(D)-及(L)-異構物可使用手性合成子或手性試劑來製備，或使用習用技術來拆分。當本文所闡述之化合物含有烯烴鍵或其他幾何不對稱性中心時，且除非另有指定，否則預期該等化合物包括E及Z幾何異構物二者。Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; mirror isomers, racemates, non-mirror isomers, tautomers, geometric isomers, stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry or as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those compounds that are known in the art to be too unstable to synthesize and/or separate. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, it is contemplated that the compounds include both E and Z geometric isomers.

如本文所用，術語「異構物」係指具有相同數量及種類之原子且由此具有相同之分子量，但關於原子之結構排列或構形有所不同之化合物。As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with respect to the structural arrangement or configuration of the atoms.

如本文所用，術語「互變異構物」係指兩種或更多種結構異構物中之一者，該等結構異構物以平衡狀態存在且易於自一種異構形式轉化成另一種異構形式。As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another.

熟習此項技術者將明瞭，本揭示案之某些化合物可以互變異構形式存在，該等化合物之所有此等互變異構形式均在本揭示案之範圍內。It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric isomeric forms and that all such tautomeric forms of the compounds are within the scope of the present disclosure.

除非另有說明，否則本文所繪示之結構亦意欲包括該結構之所有立體化學形式(亦即，每一不對稱中心之R及S構形)。因此，本發明化合物之單一立體化學異構物以及鏡像異構及非鏡像異構混合物在本揭示案之範圍內。Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure (i.e., R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as mirror and non-mirror isomeric mixtures of the compounds of the invention are within the scope of the present disclosure.

如本文所用，「手性富集群體」意指複數個具有相同分子式之分子，其中群體內在特定手性中心處含有特定立體化學構形之分子的數目或百分比大於在該特定手性中心為立體隨機的情況下群體內在相同特定手性中心處預期含有相同特定立體化學構形之分子的數目或百分比。在每一分子內具有多個手性中心之分子的手性富集群體可含有一或多個立體隨機手性中心。在某些實施例中，分子為經修飾之寡核苷酸。在某些實施例中，分子為包含經修飾之寡核苷酸之化合物。As used herein, "chirally enriched population" means a plurality of molecules having the same molecular formula, wherein the number or percentage of molecules within the population containing a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules within the population that would be expected to contain the same particular stereochemical configuration at the same particular chiral center if the particular chiral center were stereorandom. A chirally enriched population of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In some embodiments, the molecule is a modified oligonucleotide. In some embodiments, the molecule is a compound comprising a modified oligonucleotide.

除非另有說明，否則本文所繪示之結構亦意欲包括不同之處僅在於存在一或多個同位素富集原子之化合物。舉例而言，除用氘或氚置換氫或用¹³C或¹⁴C富集碳置換碳外具有本發明結構之化合物在本揭示案之範圍內。Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen with a deuterium or tritium, or the replacement of a carbon with^a13C-or14C -enriched carbon are within the scope of this disclosure.

如本文所用，「立體隨機手性中心」在具有相同分子式之分子群體背景下意指具有隨機立體化學構形之手性中心。舉例而言，在包含立體隨機手性中心之分子群體中，具有立體隨機手性中心(S)構形之分子的數目可與具有立體隨機手性中心(R)構形之分子的數目相同，但不一定相同。當手性中心之立體化學構形係並非為控制立體化學構形而設計之合成方法的結果時，可將其視為隨機的。在某些實施例中，立體隨機手性中心為立體隨機硫代磷酸酯核苷間鍵聯。某些實施例As used herein, "stereo-random chiral center" in the context of a population of molecules having the same molecular formula means a chiral center with a random stereochemical configuration. For example, in a population of molecules comprising a stereo-random chiral center, the number of molecules with a stereo-random chiral center (S) configuration may be the same as the number of molecules with a stereo-random chiral center (R) configuration, but is not necessarily the same. The stereochemical configuration of a chiral center can be considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, the stereo-random chiral center is a stereo-random phosphorothioate internucleoside linkage.Certain Embodiments

在某些態樣中，本揭示案係關於抑制LRRK2之方法、化合物及組合物。在某些實施例中，LRRK2特異性地受到抑制。在某些實施例中，LRRK2特異性地降解。在某些實施例中，LRRK2表現受到抑制。在某些實施例中，LRRK2轉譯受到抑制。在某些實施例中，LRRK2活性受到抑制。在某些實施例中，相對於未經處理或對照樣品中之表現、轉譯或活性，LRRK2表現、轉譯或活性降低至少10%。舉例而言，在某些實施例中，相對於未經處理或對照樣品中之表現、轉譯或活性，LRRK2表現、轉譯或活性降低至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、10%-50%、25%-50%、25%-75%、50%-75%、50%-99%或75%-99%。在某些實施例中，如藉由任何適宜分析所量測，LRRK2表現、轉譯或活性降低，該適宜分析包括(但不限於)免疫分析、基於雜交之分析或基於測序之分析(例如RNA-Seq)。In certain aspects, the disclosure relates to methods, compounds, and compositions for inhibiting LRRK2. In certain embodiments, LRRK2 is specifically inhibited. In certain embodiments, LRRK2 is specifically degraded. In certain embodiments, LRRK2 expression is inhibited. In certain embodiments, LRRK2 translation is inhibited. In certain embodiments, LRRK2 activity is inhibited. In certain embodiments, LRRK2 expression, translation, or activity is reduced by at least 10% relative to expression, translation, or activity in an untreated or control sample. For example, in some embodiments, LRRK2 expression, translation or activity is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10%-50%, 25%-50%, 25%-75%, 50%-75%, 50%-99% or 75%-99% relative to expression, translation or activity in an untreated or control sample. In some embodiments, LRRK2 expression, translation or activity is reduced as measured by any suitable assay, including but not limited to an immunoassay, a hybridization-based assay, or a sequencing-based assay (e.g., RNA-Seq).

在某些態樣中，本揭示案係關於靶向LRRK2核酸之化合物。在某些實施例中，LRRK2核酸具有GenBank登錄號NM_198578.4 (以SEQ ID NO: 1併入本文中)，及NG_011709.2之核苷酸5002至149290 (以SEQ ID NO: 2併入本文中)中所示之序列。In certain aspects, the disclosure relates to compounds targeting LRRK2 nucleic acids. In certain embodiments, the LRRK2 nucleic acid has a sequence as shown in GenBank Accession No. NM_198578.4 (incorporated herein as SEQ ID NO: 1), and nucleotides 5002 to 149290 of NG_011709.2 (incorporated herein as SEQ ID NO: 2).

在某些實施例中，化合物為寡聚化合物。在某些實施例中，化合物係單股的。在某些實施例中，化合物係雙股的。In some embodiments, the compound is an oligomeric compound. In some embodiments, the compound is single-stranded. In some embodiments, the compound is double-stranded.

某些實施例提供包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)之化合物，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44或83-89之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。Certain embodiments provide compounds comprising a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-44 or 83-89.

某些實施例提供包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)之化合物，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。Certain embodiments provide compounds comprising a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89.

某些實施例提供包含經修飾之寡核苷酸之化合物，該經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89中之任一者組成之群的核鹼基序列。Certain embodiments provide a compound comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89.

在某些實施例中，經修飾之寡核苷酸與SEQ ID NO: 1或2至少80%、至少85%、至少90%或至少95%互補。在某些實施例中，經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。在某些實施例中，化合物係雙股的。In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO: 1 or 2. In certain embodiments, the modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the compound is double-stranded.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments provide compounds comprising: a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide.

在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含表2及表3中所提供之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of the nucleobase sequences provided in Tables 2 and 3; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments provide compounds comprising: a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments provide compounds comprising: a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其包含5'-膦酸酯修飾，其中該第一經修飾之寡核苷酸與SEQ ID NO: 1或2之區域至少80%互補；及第二經修飾之寡核苷酸，其包含一或多種本文所闡述之配位體(例如，一或多種原肌凝蛋白受體B (TrkB)配位體)。在某些實施例中，第一經修飾之寡核苷酸包含含有5'-膦酸酯修飾之5'末端核苷。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。Certain embodiments provide compounds comprising: a first modified oligonucleotide comprising a 5'-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1 or 2; and a second modified oligonucleotide comprising one or more ligands described herein (e.g., one or more tropomyosin receptor B (TrkB) ligands). In certain embodiments, the first modified oligonucleotide comprises a 5' terminal nucleoside containing a 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification.

在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群的核鹼基序列。In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-44 and 83-89; and a second modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96.

在某些實施例中，任一前述化合物之經修飾之寡核苷酸或第一經修飾之寡核苷酸在其長度上與SEQ ID NO: 1或2具有至少80%、至少85%、至少90%或至少95%之互補性或一致性。在某些實施例中，經修飾之寡核苷酸或第一經修飾之寡核苷酸與SEQ ID NO: 1或2之區域具有至少1個、至少2個、至少3個失配。在某些實施例中，第一經修飾之寡核苷酸或第一股與第二經修飾之寡核苷酸或第二股之間的互補區長度為14至30個連接核苷。在某些實施例中，第一經修飾之寡核苷酸或第一股與第二經修飾之寡核苷酸或第二股之間的互補區長度為14至23個連接核苷。在某些實施例中，第一經修飾之寡核苷酸或第一股與第二經修飾之寡核苷酸或第二股之間的互補區長度為19至23個連接核苷。在某些實施例中，第一經修飾之寡核苷酸或第一股與第二經修飾之寡核苷酸或第二股之間的互補區長度為21至23個連接核苷。在某些實施例中，第一經修飾之寡核苷酸與第二經修飾之寡核苷酸完全互補。In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide of any of the foregoing compounds has at least 80%, at least 85%, at least 90%, or at least 95% complementarity or identity with SEQ ID NO: 1 or 2 in its length. In certain embodiments, the modified oligonucleotide or the first modified oligonucleotide has at least 1, at least 2, or at least 3 mismatches with a region of SEQ ID NO: 1 or 2. In certain embodiments, the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 14 to 30 linked nucleosides in length. In certain embodiments, the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 14 to 23 linked nucleosides in length. In certain embodiments, the complementary region between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 19 to 23 linked nucleosides in length. In certain embodiments, the complementary region between the first modified oligonucleotide or first strand and the second modified oligonucleotide or second strand is 21 to 23 linked nucleosides in length. In certain embodiments, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

在某些實施例中，任一前述化合物之經修飾之寡核苷酸或第一經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。在某些實施例中，任一前述化合物之第二經修飾之寡核苷酸包含至少一種選自由經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基組成之群的修飾。在某些實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或甲基膦酸酯核苷間鍵聯。在某些實施例中，硫代磷酸酯核苷間鍵聯或甲基膦酸酯核苷間鍵聯位於第一或第二經修飾之寡核苷酸之3’末端或位於第一經修飾之寡核苷酸之5’末端。在某些實施例中，經修飾之糖包含選自由鹵素、烷氧基及雙環糖組成之群的修飾。在某些實施例中，經修飾之糖包含2’-F修飾。在某些實施例中，經修飾之糖包含2’-OMe修飾。在某些實施例中，第一經修飾之寡核苷酸之每一核苷包含經修飾之糖。在某些實施例中，第二經修飾之寡核苷酸之每一核苷包含經修飾之糖。在某些實施例中，經修飾之糖包含選自由鹵素、烷氧基及雙環糖或其組合組成之群的修飾。在某些實施例中，經修飾之糖包含選自由2’-MOE、2’-F及2’-OMe或其組合組成之群的修飾。在某些實施例中，第一經修飾之寡核苷酸包含不超過十個2’-F糖修飾。在某些實施例中，第二經修飾之寡核苷酸包含不超過五個2’-F糖修飾。In certain embodiments, a modified oligonucleotide or a first modified oligonucleotide of any of the aforementioned compounds comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, a second modified oligonucleotide of any of the aforementioned compounds comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage. In certain embodiments, the phosphorothioate internucleoside linkage or the methylphosphonate internucleoside linkage is located at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugars. In certain embodiments, the modified sugar comprises a 2'-F modification. In certain embodiments, the modified sugar comprises a 2'-OMe modification. In certain embodiments, each nucleoside of the first modified oligonucleotide comprises a modified sugar. In certain embodiments, each nucleoside of the second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugars or a combination thereof. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of 2'-MOE, 2'-F and 2'-OMe or a combination thereof. In certain embodiments, the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

在某些實施例中，任一前述實施例之化合物包含結合基團。在某些實施例中，結合基團連接至經修飾之寡核苷酸之5’端。在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包含一或多種TrkB配位體。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。在某些實施例中，該一或多種TrkB配位體連接在寡核苷酸之5’端或3’端，或寡核苷酸之5’端及3’端。In some embodiments, the compound of any of the foregoing embodiments comprises a binding group. In some embodiments, the binding group is attached to the 5' end of the modified oligonucleotide. In some embodiments, the binding group is a targeting moiety. In some embodiments, the targeting moiety comprises one or more TrkB ligands. In some embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In some embodiments, the one or more TrkB ligands are attached to the 5' end or the 3' end of the oligonucleotide, or to the 5' end and the 3' end of the oligonucleotide.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(I)或為其鹽、溶劑合物或水合物：式(I)， 其中： R¹為經修飾之寡核苷酸； L¹、L²、L³及L⁴係如本文所闡述； R²為氫、-OR⁷、-SR⁸或-NR⁹R¹⁰； R³為氫、-OR¹¹、-SR¹²或-NR¹³R¹⁴； R⁴為氫、-OR¹⁵、-SR¹⁶或-NR¹⁷R¹⁸； R⁵為氫、-OR¹⁹、-SR²⁰或-NR²¹R²²； R⁶為氫、-OH、視情況經取代之-O-烷基、視情況經取代之-OAc、-NH₂、視情況經取代之-NHAc、-SH或=O； R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹及R²²各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基、視情況經取代之雜芳基； Y為CH₂、NH、S或O；且 Z為視情況經取代之芳基或視情況經取代之雜芳基。In certain embodiments, the TrkB ligand of the modified oligonucleotide has formula (I) or is a salt, solvate or hydrate thereof: Formula (I), wherein: R¹ is a modified oligonucleotide; L¹ , L² , L³ and L⁴ are as described herein; R² is hydrogen, -OR⁷ , -SR⁸ or -NR⁹ R¹⁰ ; R³ is hydrogen, -OR¹¹ , -SR¹² or -NR¹³ R¹⁴ ; R⁴ is hydrogen, -OR¹⁵ , -SR¹⁶ or -NR¹⁷ R¹⁸ ; R⁵ is hydrogen, -OR¹⁹ , -SR²⁰ or -NR²¹ R²² ; R⁶ is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH₂ , optionally substituted -NHAc, -SH or =O; R⁷ , R⁸ , R⁹ , R^R10 ,^R11 ,^R12 ,^R13 ,^R14 ,^R15 ,^R16 ,^R17 ,^R18 ,^R19 ,^R20 ,^R21 and^R22 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; Y is_CH2 , NH, S or O; and Z is optionally substituted aryl or optionally substituted heteroaryl.

在某些實施例中，R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹及R²²各自獨立地為視情況經取代之不飽和或部分不飽和烷基。在某些實施例中，R⁷、R⁸、R⁹及R¹⁰各自獨立地為烯基。在某些實施例中，R⁷、R⁸、R⁹及R¹⁰各自獨立地為炔基。In certain embodiments, R⁷ , R⁸ , R⁹ , R¹⁰ , R¹¹ , R¹² , R¹³ , R¹⁴ , R¹⁵ , R¹⁶ , R¹⁷ , R¹⁸ , R¹⁹ , R²⁰ , R²¹ and R²² are each independently an optionally substituted unsaturated or partially unsaturated alkyl group. In certain embodiments, R⁷ , R⁸ , R⁹ and R¹⁰ are each independently an alkenyl group. In certain embodiments, R⁷ , R⁸ , R⁹ and R¹⁰ are each independently an alkynyl group.

在某些實施例中，R²為OR⁷。在某些實施例中，R³為OR¹¹。在某些實施例中，R⁷及R¹¹各自獨立地為氫、視情況經取代之烷基或視情況經取代之烯基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為氫。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為視情況經取代之烷基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為視情況經取代之不飽和或部分不飽和烷基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為烯基。在某些實施例中，R⁷為視情況經取代之烷基且R¹¹為氫。在某些實施例中，R⁷為氫且R¹¹為視情況經取代之烷基。在某些實施例中，R⁷為烯基且R¹¹為氫。在某些實施例中，R⁷為氫且R¹¹為視情況經取代之烯基。In certain embodiments, R² is OR⁷ . In certain embodiments, R³ is OR¹¹ . In certain embodiments, R⁷ and R¹¹ are each independently hydrogen, optionally substituted alkyl, or optionally substituted alkenyl. In certain embodiments, one or both of R⁷ and R¹¹ are each independently hydrogen. In certain embodiments, one or both of R⁷ and R¹¹ are each independently hydrogen. In certain embodiments, one or both of R⁷ and R¹¹ are each independently substituted alkyl. In certain embodiments, one or both of R 7 and R 11 are each independently unsaturated or partially unsaturated alkyl, which may be substituted. In certain embodiments, one or both of R⁷ and R¹¹ are each independently alkenyl. In certain embodiments, R⁷ is optionally substituted alkyl and R¹¹ is hydrogen. In certain embodiments, R⁷ is hydrogen and R¹¹ is optionally substituted alkyl. In certain embodiments, R⁷ is alkenyl and R¹¹ is hydrogen. In certain embodiments, R⁷ is hydrogen and R¹¹ is optionally substituted alkenyl.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體係選自以下各式或其鹽、溶劑合物或水合物：式(II-A)、式(II-B)、式(II-C)， 其中： R¹為經修飾之寡核苷酸； L¹、L²、L³及L⁴係如本文所闡述。In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (II-A), Formula (II-B), Formula (II-C), wherein: R¹ is a modified oligonucleotide; L¹ , L² , L³ and L⁴ are as described herein.

在某些實施例中，L¹、L²、L³及L⁴各自獨立地不存在，為鍵、視情況經取代之烷基連接體、視情況經取代之聚乙二醇(PEG)連接體、視情況經取代之雜烷基連接體或視情況經取代之雜芳基連接體。In certain embodiments, L¹ , L² , L³ and L⁴ are each independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker or an optionally substituted heteroaryl linker.

在某些實施例中，L¹為視情況經取代之雜芳基連接體。In certain embodiments, L¹ is an optionally substituted heteroaryl linker.

在某些實施例中，L¹為視情況經取代之不飽和雜芳基、視情況經取代之雜芳基或視情況經取代之飽和或部分不飽和雜環烷基連接體。In certain embodiments, L¹ is an optionally substituted unsaturated heteroaryl, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

在某些實施例中，L¹包含結構：。In certain embodiments,^L1 comprises the structure: .

在某些實施例中，L¹為視情況經取代之雜烷基連接體。在某些實施例中，視情況經取代之雜烷基連接體為視情況經取代之雜烷基或視情況經取代之C_1-10烷基鏈，其中一或多個碳原子經O、N或S置換。In certain embodiments, L¹ is an optionally substituted heteroalkyl linker. In certain embodiments, the optionally substituted heteroalkyl linker is an optionally substituted heteroalkyl or an optionally substituted C_1-10 alkyl chain in which one or more carbon atoms are replaced by O, N or S.

在某些實施例中，L¹包含結構：或。In certain embodiments,^L1 comprises the structure: or .

在某些實施例中，L¹包含結構：或-N(CH₃)-。In certain embodiments,^L1 comprises the structure: or -N(CH₃ )-.

在某些實施例中，L²為視情況經取代之PEG連接體。In certain embodiments,^L2 is an optionally substituted PEG linker.

在某些實施例中，PEG連接體之長度為五個PEG單元。在某些實施例中，PEG連接體之長度為四個PEG單元。在某些實施例中，PEG連接體之長度為三個PEG單元。In some embodiments, the PEG conjugate is five PEG units in length. In some embodiments, the PEG conjugate is four PEG units in length. In some embodiments, the PEG conjugate is three PEG units in length.

在某些實施例中，L²為視情況經取代之烷基連接體。在某些實施例中，L²為視情況經取代之C_1-20烷基連接體。在某些實施例中，L²為視情況經取代之C₈烷基連接體。在某些實施例中，L³為視情況經取代之雜芳基連接體。In some embodiments,^L2 is an optionally substituted alkyl linker. In some embodiments,^L2 is an optionally substituted_C1-20 alkyl linker. In some embodiments,^L2 is an optionally substituted_C8 alkyl linker. In some embodiments,^L3 is an optionally substituted heteroaryl linker.

在某些實施例中，L³為視情況經取代之部分不飽和雜芳基連接體、視情況經取代之雜芳基或視情況經取代之飽和或部分不飽和雜環烷基連接體。In certain embodiments, L³ is an optionally substituted partially unsaturated heteroaryl linker, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

在某些實施例中，L³包含結構：。In certain embodiments,^L3 comprises the structure: .

在某些實施例中，L⁴為視情況經取代之雜烷基連接體。在某些實施例中，雜烷基連接體經一或多個=O取代基取代。In certain embodiments,^L4 is an optionally substituted heteroalkyl linker. In certain embodiments, the heteroalkyl linker is substituted with one or more =0 substituents.

在某些實施例中，雜烷基連接體包含兩個接合在一起形成視情況經取代之碳環基環之取代基。In certain embodiments, the heteroalkyl linker comprises two substituents joined together to form an optionally substituted carbocyclyl ring.

在某些實施例中，L⁴包含結構：或其鹽，其中X為O或S。In certain embodiments,^L4 comprises the structure: or a salt thereof, wherein X is O or S.

在某些實施例中，L⁴包含結構：或其鹽，其中X為O或S。In certain embodiments,^L4 comprises the structure: or a salt thereof, wherein X is O or S.

在某些實施例中，L¹-L²-L³-L⁴包含結構：、、、、、、、、、、、、、、、、、或其鹽，其中X為O或S。In certain embodiments, L¹ -L² -L³ -L⁴ comprises the structure: , , , , , , , , , , , , , , , , , or a salt thereof, wherein X is O or S.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體係選自以下各式或其鹽、溶劑合物或水合物：式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、式(XI)、式(XII)、式(XIII)、式(XIV)、式(XV)、式(XVI)、式(XVII)、式(XVIII)、式(XIX)、式(XX)， 其中： R為經修飾之寡核苷酸； X為S或O。In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), wherein: R is a modified oligonucleotide; X is S or O.

在某些實施例中，任一前述實施例之化合物包含脂質。在某些實施例中，脂質連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸包含一或多種脂質。在某些實施例中，該一或多種脂質連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。In certain embodiments, the compound of any of the preceding embodiments comprises a lipid. In certain embodiments, the lipid is linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more lipids. In certain embodiments, the one or more lipids are linked to one or more internucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide.

在某些實施例中，任一前述實施例之化合物包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。In certain embodiments, the compound of any of the foregoing embodiments comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide. In certain embodiments, a modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to one or more internucleoside linkages of a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide.

在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₇烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₈烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₂₂烴鏈。In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₄ -C₃₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₅ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₆ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₇ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated_C18 hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated_C22 hydrocarbon chains.

在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之末端(例如5'端及/或3'端) 10個位置內(例如8個位置內、6個位置內、5個位置內、4個位置內、3個位置內、2個位置內)的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端5個位置內的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端5個位置內的核苷之間。In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is attached to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, the internucleoside linkage is between nucleosides within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of the end (e.g., the 5' end and/or the 3' end) of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions from the 3' end of the modified oligonucleotide.

在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的2位與3位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的2位與3位之間。In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 3' end of the modified oligonucleotide.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXI-式XXIV中之任一者。In certain embodiments, the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXI-XXIV.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯包含式(XXI)，或其鹽、溶劑合物或水合物：式(XXI)， 其中： Y為-C(=O)N(R^C)-或-N(R^C)C(=O)-； Q¹及Q³各自獨立地為-H、-OR⁴、配位體、連接體或脂質； Q²及Q⁴各自獨立地為鍵、、配位體、連接體或脂質； R^C獨立地為-H、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基； 每一R⁹獨立地為經取代或未經取代之雜芳基； Z¹或Z²之每一實例獨立地為鍵、C₁-C₆伸烷基或C₂-C₆伸烯基；且 每一X獨立地為O或S； 或其鹽。In certain embodiments, the internucleoside linkage of the modified oligonucleotide comprises formula (XXI), or a salt, solvate or hydrate thereof: Formula (XXI), wherein: Y is -C(=O)N(^RC )- or -N(^RC )C(=O)-;^Q1 and^Q3 are each independently -H,^-OR4 , a ligand, a linker or a lipid;^Q2 and^Q4 are each independently a bond, , ligand, linker or lipid; R^C is independently -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently^an oligonucleotide, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently substituted or unsubstituted heteroaryl; each R⁹ is independently substituted or unsubstituted heteroaryl; each instance of Z¹ or Z² is independently a bond, C₁ -C₆ alkylene, or C₂ -C₆ alkenylene; and each X is independently O or S; or a salt thereof.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯包含式(XXII)，或其鹽、溶劑合物或水合物：式(XXII)， 其中： R^C為-H、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the internucleoside linkage of the modified oligonucleotide comprises formula (XXII), or a salt, solvate or hydrate thereof: Formula (XXII), wherein:^RC is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each^R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR6 , -N(R6), or^-SR6 ; each^R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR7 , -N(^R7 ), or^-SR7;R4 and^R5 are independently oligonucleotides, or^R4 and^R5 are joined together to form a single oligonucleotide; each R R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently substituted or unsubstituted heteroaryl ring; each R⁹ is independently substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯包含式(XXIII)，或其鹽、溶劑合物或水合物：式(XXIII)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the internucleoside linkage of the modified oligonucleotide comprises formula (XXIII), or a salt, solvate or hydrate thereof: Formula (XXIII), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯包含式(XXIV)，或其鹽、溶劑合物或水合物：式(XXIV). 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the internucleoside linkage of the modified oligonucleotide comprises formula (XXIV), or a salt, solvate or hydrate thereof: Formula (XXIV). wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，任一前述實施例之化合物包含5'-膦酸酯修飾。舉例而言，在某些實施例中，經修飾之寡核苷酸包含一或多個在5'位具有膦酸酯修飾之糖。在某些實施例中，經修飾之寡核苷酸包含5'-膦酸酯修飾。在某些實施例中，經修飾之寡核苷酸包含含有5'-膦酸酯修飾之5'末端核苷(例如5'末端)。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-伸乙基膦酸酯修飾。在某些實施例中，經修飾之寡核苷酸為第一經修飾之寡核苷酸或反義寡核苷酸。In certain embodiments, the compound of any of the foregoing embodiments comprises a 5'-phosphonate modification. For example, in certain embodiments, the modified oligonucleotide comprises one or more sugars having a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide comprises a 5'-phosphonate modification. In certain embodiments, the modified oligonucleotide comprises a 5'-terminal nucleoside (e.g., the 5' end) containing a 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-ethylphosphonate modification. In certain embodiments, the modified oligonucleotide is a first modified oligonucleotide or an antisense oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其包含5'-膦酸酯修飾，其中該第一經修飾之寡核苷酸與SEQ ID NO: 1或2之區域至少80%互補；及第二經修飾之寡核苷酸，其包含一或多種配位體。Certain embodiments provide compounds comprising: a first modified oligonucleotide comprising a 5'-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1 or 2; and a second modified oligonucleotide comprising one or more ligands.

在一些實施例中，第一經修飾之寡核苷酸包含含有5'-膦酸酯修飾之5'末端核苷。在一些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。在一些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾。在一些實施例中，5'-膦酸酯修飾為5'-伸乙基膦酸酯修飾。In some embodiments, the first modified oligonucleotide comprises a 5' terminal nucleoside containing a 5'-phosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In some embodiments, the 5'-phosphonate modification is a 5'-ethylphosphonate modification.

在一些實施例中，第二經修飾之寡核苷酸之該一或多種配位體包含一或多種TrkB配位體。在一些實施例中，該一或多種TrkB配位體連接至第二經修飾之寡核苷酸之5’端。在一些實施例中，該一或多種TrkB配位體連接至第二經修飾之寡核苷酸之3’端。在一些實施例中，該一或多種TrkB配位體連接至第二經修飾之寡核苷酸之5’端及3’端。在一些實施例中，該一或多種TrkB配位體係選自式I-式XX中之任一者。在一些實施例中，第二經修飾之寡核苷酸包含一種TrkB配位體。在一些實施例中，第二經修飾之寡核苷酸包含兩種TrkB配位體。在一些實施例中，第二經修飾之寡核苷酸包含至少兩種TrkB配位體。在一些實施例中，該至少兩種TrkB配位體係相同的。在一些實施例中，該至少兩種TrkB配位體係不同的。In some embodiments, the one or more ligands of the second modified oligonucleotide comprise one or more TrkB ligands. In some embodiments, the one or more TrkB ligands are linked to the 5' end of the second modified oligonucleotide. In some embodiments, the one or more TrkB ligands are linked to the 3' end of the second modified oligonucleotide. In some embodiments, the one or more TrkB ligands are linked to the 5' end and 3' end of the second modified oligonucleotide. In some embodiments, the one or more TrkB ligands are selected from any one of Formula I-Formula XX. In some embodiments, the second modified oligonucleotide comprises one TrkB ligand. In some embodiments, the second modified oligonucleotide comprises two TrkB ligands. In some embodiments, the second modified oligonucleotide comprises at least two TrkB ligands. In some embodiments, the at least two TrkB ligands are the same. In some embodiments, the at least two TrkB ligands are different.

在一些實施例中，第二經修飾之寡核苷酸包含一或多種脂質。在一些實施例中，第二經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。在一些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。在一些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈。在一些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。在一些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈、飽和或不飽和C₁₇烴鏈、飽和或不飽和C₁₈烴鏈或飽和或不飽和C₂₂烴鏈。In some embodiments, the second modified oligonucleotide comprises one or more lipids. In some embodiments, the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise saturated or unsaturated C₄ -C₃₀ hydrocarbon chains. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise saturated or unsaturated C₅ -C₂₀ hydrocarbon chains. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chains. In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated_C16 hydrocarbon chain, a saturated or unsaturated_C17 hydrocarbon chain, a saturated or unsaturated_C18 hydrocarbon chain, or a saturated or unsaturated_C22 hydrocarbon chain.

在一些實施例中，該一或多個經取代或未經取代之烷基或烯基連接至第二經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之末端(例如5'端及/或3'端) 10個位置內(例如8個位置內、6個位置內、5個位置內、4個位置內、3個位置內、2個位置內)的核苷之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之5'端5個位置內的核苷之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之3'端5個位置內的核苷之間。In some embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to the internucleoside linkage of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of the end (e.g., 5' end and/or 3' end) of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions from the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions from the 3' end of the second modified oligonucleotide.

在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之5'端的2位與3位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距第二經修飾之寡核苷酸之3'端的2位與3位之間。In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 5' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the second modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 3' end of the second modified oligonucleotide.

在一些實施例中，第二經修飾之寡核苷酸之核苷間鍵聯係選自式XXI-式XXIV中之任一者。In some embodiments, the internucleoside linkage of the second modified oligonucleotide is selected from any one of Formula XXI-XXIV.

在一些實施例中，第一經修飾之寡核苷酸之長度為14至30個連接核苷。在一些實施例中，第二經修飾之寡核苷酸之長度為14至30個連接核苷，其具有與第一經修飾之寡核苷酸互補之區域。在一些實施例中，第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之至少14個鄰接核鹼基之核鹼基序列。在一些實施例中，第二經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一者之至少14個鄰接核鹼基之核鹼基序列。在一些實施例中，第一經修飾之寡核苷酸係選自表3中IA Ref ID NO中之任一者。在一些實施例中，第二經修飾之寡核苷酸係選自表3中IS Ref ID NO中之任一者。In some embodiments, the length of the first modified oligonucleotide is 14 to 30 linked nucleosides. In some embodiments, the length of the second modified oligonucleotide is 14 to 30 linked nucleosides, which has a region complementary to the first modified oligonucleotide. In some embodiments, the first modified oligonucleotide has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NO: 11-44 and 83-89. In some embodiments, the second modified oligonucleotide has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NO: 45-82 and 90-96. In some embodiments, the first modified oligonucleotide is selected from any one of IA Ref ID NO in Table 3. In some embodiments, the second modified oligonucleotide is selected from any one of the IS Ref ID NOs in Table 3.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其係選自由表3中所列示之Ref ID NO中之任一者組成之群；及長度為14至21個連接核苷之第二經修飾之寡核苷酸，其與該第一經修飾之寡核苷酸完全互補。Certain embodiments provide a compound comprising: a first modified oligonucleotide selected from the group consisting of any one of the Ref ID NOs listed in Table 3; and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides that is completely complementary to the first modified oligonucleotide.

某些實施例提供包含以下之化合物：第一經修飾之寡核苷酸，其係選自由表3中所列示之IA Ref ID NO中之任一者組成之群；及第二經修飾之寡核苷酸，其係選自由表3中所列示之IS Ref ID NO中之任一者組成之群。Certain embodiments provide a compound comprising: a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs listed in Table 3; and a second modified oligonucleotide selected from the group consisting of any one of the IS Ref ID NOs listed in Table 3.

在某些實施例中，本文所提供之經修飾之寡核苷酸的醫藥學上可接受之鹽為鈉鹽或鉀鹽。在某些實施例中，本文所提供化合物之醫藥學上可接受之鹽為鈉鹽或鉀鹽。In certain embodiments, the pharmaceutically acceptable salt of the modified oligonucleotides provided herein is a sodium salt or a potassium salt. In certain embodiments, the pharmaceutically acceptable salt of the compounds provided herein is a sodium salt or a potassium salt.

在某些實施例中，本文提供經修飾之寡核苷酸群體，其中經修飾之寡核苷酸之所有硫代磷酸酯核苷間鍵聯均為立體隨機的。在某些實施例中，本文提供化合物群體，其中經修飾之寡核苷酸之所有硫代磷酸酯核苷間鍵聯均為立體隨機的。In certain embodiments, provided herein are populations of modified oligonucleotides, wherein all phosphorothioate internucleoside linkages of the modified oligonucleotides are stereo-random. In certain embodiments, provided herein are populations of compounds, wherein all phosphorothioate internucleoside linkages of the modified oligonucleotides are stereo-random.

在某些實施例中，任一前述實施例之化合物係呈醫藥學上可接受之鹽形式。在某些實施例中，醫藥學上可接受之鹽為鈉鹽。在某些實施例中，醫藥學上可接受之鹽為鉀鹽。In some embodiments, the compound of any of the foregoing embodiments is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, the pharmaceutically acceptable salt is a potassium salt.

某些實施例提供組合物，其包含如前述實施例中任一項之化合物以及醫藥學上可接受之載劑。Certain embodiments provide a composition comprising a compound as described in any of the preceding embodiments and a pharmaceutically acceptable carrier.

某些實施例提供包含任一前述實施例之化合物之組合物，其用於療法中。Certain embodiments provide a composition comprising a compound of any preceding embodiment for use in therapy.

某些實施例提供治療、預防或改善個體之與LRRK2相關的疾病、病症或疾患之方法，其包括向該個體投與靶向LRRK2之化合物，藉此治療、預防或改善該疾病。Certain embodiments provide methods for treating, preventing or ameliorating a disease, disorder or condition associated with LRRK2 in a subject, comprising administering to the subject a compound that targets LRRK2, thereby treating, preventing or ameliorating the disease.

在某些實施例中，向個體投與任一前述實施例之化合物或組合物。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。In some embodiments, a compound or composition of any of the preceding embodiments is administered to a subject. In some embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation, and neuronal death.

在某些實施例中，投與化合物抑制或減少或改善CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。In certain embodiments, administration of the compound inhibits or reduces or ameliorates a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation, and neuronal death.

在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以治療有效量投與給個體。在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以足以遞送約1至100 mg/kg個體體重之劑量水準投與給個體。在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以約25 mg至約1,000 mg之固定劑量投與給個體。在某些實施例中，在一天內向個體投與一或多次化合物或組合物，直至該劑量水準或固定劑量。In certain embodiments, a compound or a composition comprising a compound of any of the foregoing embodiments is administered to a subject in a therapeutically effective amount. In certain embodiments, a compound or a composition comprising a compound of any of the foregoing embodiments is administered to a subject at a dosage level sufficient to deliver about 1 to 100 mg/kg of the subject's body weight. In certain embodiments, a compound or a composition comprising a compound of any of the foregoing embodiments is administered to a subject at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, a compound or composition is administered to a subject one or more times a day up to the dosage level or fixed dose.

在某些實施例中，每天、每週、每月、每季度或每年向個體投與化合物或包含任一前述實施例之化合物之組合物。在某些實施例中，約每季度一次(亦即每三個月一次)至約每年一次向個體投與化合物或包含任一前述實施例之化合物之組合物。在某些實施例中，約每季度一次、約每六個月一次或約每年一次向個體投與化合物或包含任一前述實施例之化合物之組合物。In certain embodiments, a compound or a composition comprising a compound of any of the preceding embodiments is administered to a subject daily, weekly, monthly, quarterly, or annually. In certain embodiments, a compound or a composition comprising a compound of any of the preceding embodiments is administered to a subject about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, a compound or a composition comprising a compound of any of the preceding embodiments is administered to a subject about once a quarter, about once every six months, or about once a year.

某些實施例提供抑制細胞中之LRRK2表現之方法，其包括使該細胞與靶向LRRK2之化合物接觸，藉此抑制該細胞中之LRRK2表現。在某些實施例中，細胞在個體之肝臟中。在某些實施例中，個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡，或處於患有此類疾病、病症或疾患或其症狀之風險下。Certain embodiments provide methods of inhibiting LRRK2 expression in a cell, comprising contacting the cell with a compound that targets LRRK2, thereby inhibiting LRRK2 expression in the cell. In certain embodiments, the cell is in the liver of an individual. In certain embodiments, the individual suffers from a CNS-related disease, disorder, or condition, or a symptom thereof, or a neurodegenerative disease, or a symptom thereof, including Parkinson's disease or cognitive impairment, or a symptom thereof, such as loss of motor function, aggregate formation, and neuronal death, or is at risk of suffering from such a disease, disorder, or condition, or a symptom thereof.

某些實施例提供減少或抑制個體之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀、包括帕金森氏病或認知損害或其症狀(諸如運動功能喪失、聚集體形成及神經元死亡)之方法，其包括向該個體投與靶向LRRK2之化合物，藉此減少或抑制該個體之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，化合物為靶向LRRK2之化合物。在某些實施例中，化合物為前述化合物中之任一者。在某些實施例中，非經腸投與化合物或組合物。在某些實施例中，藉由鞘內(IT)投與來投與化合物或組合物。Certain embodiments provide methods of reducing or inhibiting a CNS-related disease, disorder or condition or symptoms thereof, or a neurodegenerative disease or symptom thereof, including Parkinson's disease or cognitive impairment or symptoms thereof (such as loss of motor function, aggregate formation, and neuronal death) in a subject, comprising administering to the subject a compound that targets LRRK2, thereby reducing or inhibiting the CNS-related disease, disorder or condition or symptoms thereof, or a neurodegenerative disease or symptom thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation, and neuronal death in the subject. In certain embodiments, the individual suffers from a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation and neuronal death, or is at risk of suffering from such a disease, disorder or condition or symptoms thereof. In certain embodiments, the compound is a compound that targets LRRK2. In certain embodiments, the compound is any of the aforementioned compounds. In certain embodiments, the compound or composition is administered parenterally. In certain embodiments, the compound or composition is administered by intrathecal (IT) administration.

某些實施例提供靶向LRRK2之化合物之用途，其用於治療、預防或改善與LRRK2相關之疾病、病症或疾患。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，化合物為靶向LRRK2之化合物。在某些實施例中，化合物為前述化合物中之任一者。Certain embodiments provide the use of compounds targeting LRRK2 for treating, preventing or ameliorating diseases, disorders or conditions associated with LRRK2. In certain embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including Parkinson's disease or cognitive impairment or a symptom thereof, such as motor function loss, aggregate formation and neuronal death. In certain embodiments, the compound is a compound targeting LRRK2. In certain embodiments, the compound is any one of the aforementioned compounds.

某些實施例提供靶向LRRK2之化合物之用途，其用於製造用以治療、預防或改善與LRRK2相關之疾病、病症或疾患的藥劑。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，化合物為靶向LRRK2之化合物。在某些實施例中，化合物為前述化合物中之任一者。某些適應症Certain embodiments provide the use of compounds targeting LRRK2 for the manufacture of a medicament for treating, preventing or ameliorating a disease, disorder or condition associated with LRRK2. In certain embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including Parkinson's disease or cognitive impairment or a symptom thereof, such as loss of motor function, aggregate formation and neuronal death. In certain embodiments, the compound is a compound targeting LRRK2. In certain embodiments, the compound is any one of the aforementioned compounds.Certain Indications

在某些態樣中，本揭示案係關於藉由投與靶向LRRK2之化合物而抑制LRRK2表現之方法，其可用於治療、預防或改善個體之與LRRK2相關之疾病。在某些實施例中，化合物可為LRRK2特異性抑制劑。在某些實施例中，化合物可為靶向LRRK2之反義寡核苷酸、寡聚化合物或寡核苷酸。In certain aspects, the present disclosure relates to methods of inhibiting LRRK2 expression by administering a compound targeting LRRK2, which can be used to treat, prevent or ameliorate a disease associated with LRRK2 in an individual. In certain embodiments, the compound can be an LRRK2 specific inhibitor. In certain embodiments, the compound can be an antisense oligonucleotide, an oligomeric compound or an oligonucleotide targeting LRRK2.

在某些態樣中，本揭示案係關於治療、預防或改善與LRRK2相關之疾病、病症或疾患。在某些實施例中，本文所提供之方法可治療、可預防及/或可改善之與LRRK2相關之疾病、病症或疾患包括CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。本文所提供之某些化合物係關於減少動物之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀、包括帕金森氏病或認知損害或其症狀(諸如運動功能喪失、聚集體形成及神經元死亡)之化合物及組合物。In certain aspects, the disclosure relates to treating, preventing or ameliorating diseases, disorders or conditions associated with LRRK2. In certain embodiments, the methods provided herein treat, prevent and/or ameliorate diseases, disorders or conditions associated with LRRK2, including CNS-related diseases, disorders or conditions or symptoms thereof or neurodegenerative diseases or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation and neuronal death. Certain compounds provided herein relate to compounds and compositions that reduce CNS-related diseases, disorders or conditions or symptoms thereof or neurodegenerative diseases or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation and neuronal death in animals.

在某些實施例中，治療、預防或改善個體之與LRRK2相關之疾病的方法包括向該個體投與包含LRRK2特異性抑制劑之化合物，藉此治療、預防或改善該疾病。在某些實施例中，個體鑑別為患有與LRRK2相關之疾病，或處於患有該疾病之風險下。在某些實施例中，疾病為CNS相關之疾病。在某些實施例中，化合物包含靶向LRRK2之反義寡核苷酸。在某些實施例中，化合物包含靶向LRRK2之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在某些實施例中，單股化合物之長度可為14至30個、14至23個、14至20個、16至20個或14至16個連接核苷。在某些實施例中，單股化合物之長度可為14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個連接核苷。在某些實施例中，如本文中別處所闡述，雙股化合物可包含兩個相同或不同長度之寡核苷酸。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，將化合物非經腸投與給個體。在某些實施例中，藉由鞘內(IT)投與將化合物投與給個體。在某些實施例中，投與化合物改進、保持或預防動物之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。In certain embodiments, a method for treating, preventing or ameliorating a disease associated with LRRK2 in an individual comprises administering to the individual a compound comprising a specific inhibitor of LRRK2, thereby treating, preventing or ameliorating the disease. In certain embodiments, the individual is identified as having a disease associated with LRRK2, or is at risk of having the disease. In certain embodiments, the disease is a CNS-related disease. In certain embodiments, the compound comprises an antisense oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises an oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-44 and 83-89; and a second modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In some embodiments, the length of a single-stranded compound may be 14 to 30, 14 to 23, 14 to 20, 16 to 20, or 14 to 16 linked nucleosides. In certain embodiments, the length of a single-stranded compound may be 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 linked nucleosides. In certain embodiments, as described elsewhere herein, a double-stranded compound may comprise two oligonucleotides of the same or different lengths. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to the subject parenterally. In certain embodiments, the compound is administered to the subject by intrathecal (IT) administration. In certain embodiments, administration of the compound improves, maintains or prevents a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof in an animal, including Parkinson's disease or cognitive impairment or a symptom thereof, such as loss of motor function, aggregate formation and neuronal death.

在某些實施例中，治療、預防或改善動物之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀、包括帕金森氏病或認知損害或其症狀(諸如運動功能喪失、聚集體形成及神經元死亡)之方法包括向個體投與包含LRRK2特異性抑制劑之化合物，藉此治療、預防或改善CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，化合物包含靶向LRRK2之反義寡核苷酸。在某些實施例中，化合物包含靶向LRRK2之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，投與化合物改進、保持或預防動物之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，個體鑑別為患有與LRRK2相關之疾病，或處於患有該疾病之風險下。In certain embodiments, a method of treating, preventing or ameliorating a CNS-related disease, disorder or condition or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including Parkinson's disease or cognitive impairment or a symptom thereof (such as loss of motor function, aggregate formation and neuronal death) in an animal comprises administering to an individual a compound comprising a specific inhibitor of LRRK2, thereby treating, preventing or ameliorating a CNS-related disease, disorder or condition or a symptom thereof, or a neurodegenerative disease or a symptom thereof, including Parkinson's disease or cognitive impairment or a symptom thereof, such as loss of motor function, aggregate formation and neuronal death. In certain embodiments, the compound comprises an antisense oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises an oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-44 and 83-89; and a second modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, administration of the compound improves, maintains or prevents a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof in an animal, including Parkinson's disease or cognitive impairment or a symptom thereof, such as loss of motor function, aggregate formation and neuronal death. In certain embodiments, the individual is identified as having, or at risk for having, a disease associated with LRRK2.

在某些實施例中，抑制患有與LRRK2相關之疾病或處於患有該疾病之風險下的個體中之LRRK2表現之方法包括向該個體投與包含LRRK2特異性抑制劑之化合物，藉此抑制該個體中之LRRK2表現。在某些實施例中，投與化合物抑制肝臟中之LRRK2表現。在某些實施例中，疾病為CNS相關之疾病。在某些實施例中，個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，化合物包含靶向LRRK2之反義寡核苷酸。在某些實施例中，化合物包含靶向LRRK2之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，將化合物非經腸投與給個體。在某些實施例中，藉由鞘內(IT)投與將化合物投與給個體。在某些實施例中，投與化合物改進、保持或預防CNS相關之疾病、病症或疾患或其症狀、神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。In certain embodiments, a method of inhibiting LRRK2 expression in an individual suffering from or at risk of suffering from a disease associated with LRRK2 comprises administering to the individual a compound comprising a specific inhibitor of LRRK2, thereby inhibiting LRRK2 expression in the individual. In certain embodiments, administration of the compound inhibits LRRK2 expression in the liver. In certain embodiments, the disease is a CNS-related disease. In certain embodiments, the individual suffers from a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation and neuronal death, or is at risk of suffering from such a disease, disorder or condition or symptoms thereof. In certain embodiments, the compound comprises an antisense oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises an oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-44 and 83-89; and a second modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to the subject parenterally. In certain embodiments, the compound is administered to the subject by intrathecal (IT) administration. In certain embodiments, administration of the compound improves, maintains or prevents CNS-related diseases, disorders or conditions or symptoms thereof, neurodegenerative diseases or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation and neuronal death.

在某些實施例中，抑制細胞中之LRRK2表現之方法包括使該細胞與包含LRRK2特異性抑制劑之化合物接觸，藉此抑制該細胞中之LRRK2表現。在某些實施例中，細胞為肝細胞。在某些實施例中，細胞在肝臟中。在某些實施例中，細胞在個體之肝臟中，該個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，化合物包含靶向LRRK2之反義寡核苷酸。在某些實施例中，化合物包含靶向LRRK2之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。In certain embodiments, the method of inhibiting LRRK2 expression in a cell comprises contacting the cell with a compound comprising a specific inhibitor of LRRK2, thereby inhibiting LRRK2 expression in the cell. In certain embodiments, the cell is a hepatocyte. In certain embodiments, the cell is in the liver. In certain embodiments, the cell is in the liver of an individual who suffers from a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including Parkinson's disease or cognitive impairment or a symptom thereof, such as loss of motor function, aggregate formation and neuronal death, or is at risk of suffering from such a disease, disorder or condition or a symptom thereof. In certain embodiments, the compound comprises an antisense oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises an oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-44 and 83-89; and a second modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

在某些實施例中，減少或抑制患有與LRRK2相關之疾病或處於患有該疾病之風險下的個體之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀、包括帕金森氏病或認知損害或其症狀(諸如運動功能喪失、聚集體形成及神經元死亡)之方法包括向該個體投與包含LRRK2特異性抑制劑之化合物，藉此減少或抑制該個體之CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，個體患有CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，化合物包含靶向LRRK2之反義寡核苷酸。在某些實施例中，化合物包含靶向LRRK2之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，將化合物非經腸投與給個體。在某些實施例中，藉由鞘內(IT)投與將化合物投與給個體。在某些實施例中，個體鑑別為患有與LRRK2相關之疾病，或處於患有該疾病之風險下。In certain embodiments, a method of reducing or inhibiting a CNS-related disease, disorder or condition or symptoms thereof, or a neurodegenerative disease or symptom thereof, including Parkinson's disease, or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation, and neuronal death, in a subject having or at risk of having a disease associated with LRRK2 comprises administering to the subject a compound comprising a specific inhibitor of LRRK2, thereby reducing or inhibiting the CNS-related disease, disorder or condition or symptoms thereof, or a neurodegenerative disease or symptom thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation, and neuronal death in the subject. In certain embodiments, the subject has, or is at risk for, a CNS-related disease, disorder or condition or symptoms thereof, or a neurodegenerative disease or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation, and neuronal death. In certain embodiments, the compound comprises an antisense oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises an oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-44 and 83-89; and a second modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide of 19 to 23 linked nucleosides in length having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to the subject parenterally. In certain embodiments, the compound is administered to the subject by intrathecal (IT) administration. In certain embodiments, the subject is identified as having, or at risk for, a disease associated with LRRK2.

某些實施例係關於包含LRRK2特異性抑制劑之化合物，其用於治療與LRRK2相關之疾病、病症或疾患。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，化合物包含靶向LRRK2之反義寡核苷酸。在某些實施例中，化合物包含靶向LRRK2之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，將化合物非經腸投與給個體。在某些實施例中，藉由鞘內(IT)投與將化合物投與給個體。Certain embodiments relate to compounds comprising LRRK2 specific inhibitors for use in treating diseases, disorders or conditions associated with LRRK2. In certain embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or a symptom thereof or a neurodegenerative disease or a symptom thereof, including Parkinson's disease or cognitive impairment or a symptom thereof, such as motor function loss, aggregate formation and neuronal death. In certain embodiments, the compound comprises an antisense oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises an oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-44 and 83-89; and a second modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound is administered to a subject parenterally. In certain embodiments, the compound is administered to a subject by intrathecal (IT) administration.

某些實施例係關於包含LRRK2特異性抑制劑之化合物，其用於減少或抑制CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，化合物包含靶向LRRK2之反義寡核苷酸。在某些實施例中，化合物包含靶向LRRK2之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments relate to compounds comprising specific inhibitors of LRRK2 for use in reducing or inhibiting CNS-related diseases, disorders or conditions or symptoms thereof or neurodegenerative diseases or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as motor function loss, aggregate formation and neuronal death. In certain embodiments, the compound comprises an antisense oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises an oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

某些實施例係關於包含LRRK2特異性抑制劑之化合物之用途，其用於製造或製備用以治療與LRRK2相關之疾病之藥劑。某些實施例係關於包含LRRK2特異性抑制劑之化合物之用途，其用於製備用以治療與LRRK2相關之疾病、病症或疾患之藥劑。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀。在某些實施例中，疾病、病症或疾患為神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，化合物包含靶向LRRK2之反義寡核苷酸。在某些實施例中，化合物包含靶向LRRK2之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments relate to the use of a compound comprising a specific inhibitor of LRRK2 for the manufacture or preparation of a medicament for treating a disease associated with LRRK2. Certain embodiments relate to the use of a compound comprising a specific inhibitor of LRRK2 for the preparation of a medicament for treating a disease, disorder or condition associated with LRRK2. In certain embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or a symptom thereof. In certain embodiments, the disease, disorder or condition is a neurodegenerative disease or a symptom thereof, including Parkinson's disease or cognitive impairment or a symptom thereof, such as loss of motor function, aggregate formation, and neuronal death. In certain embodiments, the compound comprises an antisense oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises an oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-44 and 83-89; and a second modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

某些實施例係關於包含LRRK2特異性抑制劑之化合物之用途，其用於製造或製備用以減少或抑制個體之CNS相關之疾病、病症或疾患或其症狀的藥劑，該個體患有與LRRK2相關之CNS相關之疾病、病症或疾患或其症狀，或處於患有此類疾病、病症或疾患或其症狀之風險下。在某些實施例中，CNS相關之疾病、病症或疾患為神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。某些實施例係關於包含LRRK2特異性抑制劑之化合物之用途，其用於製備用以治療與LRRK2相關之疾病、病症或疾患之藥劑。在某些實施例中，疾病、病症或疾患為CNS相關之疾病、病症或疾患或其症狀或者神經退化性疾病或其症狀，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。在某些實施例中，化合物包含靶向LRRK2之反義寡核苷酸。在某些實施例中，化合物包含靶向LRRK2之寡核苷酸。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，且該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，該經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群。在某些實施例中，化合物包含經修飾之寡核苷酸，該經修飾之寡核苷酸係選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群。在某些實施例中，化合物包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89之核鹼基序列組成之群的核鹼基序列；及第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有選自由SEQ ID NO: 45-82及90-96之核鹼基序列組成之群的核鹼基序列。在任一前述實施例中，化合物可為單股或雙股的。在任一前述實施例中，化合物可為反義寡核苷酸或寡聚化合物。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有包含SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及第二經修飾之寡核苷酸(例如，長度為14至30個、例如14至23個連接核苷)，其具有與該第一經修飾之寡核苷酸互補之區域。在某些實施例中，化合物包含第一經修飾之寡核苷酸，其具有選自由SEQ ID NO: 11-44及83-89或SEQ ID NO: 45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，其具有與該第一經修飾之寡核苷酸互補之區域。Certain embodiments relate to the use of a compound comprising a specific inhibitor of LRRK2 for the manufacture or preparation of a medicament for reducing or inhibiting a CNS-related disease, disorder or condition or a symptom thereof in an individual who suffers from or is at risk of suffering from a CNS-related disease, disorder or condition or a symptom thereof associated with LRRK2. In certain embodiments, the CNS-related disease, disorder or condition is a neurodegenerative disease or a symptom thereof, including Parkinson's disease or cognitive impairment or a symptom thereof, such as loss of motor function, aggregate formation, and neuronal death. Certain embodiments relate to the use of a compound comprising a specific inhibitor of LRRK2 for the preparation of a medicament for treating a disease, disorder or condition associated with LRRK2. In certain embodiments, the disease, disorder or condition is a CNS-related disease, disorder or condition or symptoms thereof or a neurodegenerative disease or symptoms thereof, including Parkinson's disease or cognitive impairment or symptoms thereof, such as motor function loss, aggregate formation and neuronal death. In certain embodiments, the compound comprises an antisense oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises an oligonucleotide targeting LRRK2. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleobases of any one of the nucleobase sequences of SEQ ID NOs: 45-82 and 90-96. In certain embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of the nucleobase sequences of SEQ ID NOs: 11-44 and 83-89. In some embodiments, the compound comprises a modified oligonucleotide selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In some embodiments, the compound comprises a first modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 11-44 and 83-89; and a second modified oligonucleotide having a nucleotide sequence selected from the group consisting of nucleotide sequences of SEQ ID NOs: 45-82 and 90-96. In any of the foregoing embodiments, the compound may be single-stranded or double-stranded. In any of the foregoing embodiments, the compound may be an antisense oligonucleotide or an oligomeric compound. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleosides in length) having a region complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or SEQ ID NOs: 45-82 and 90-96; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides having a region complementary to the first modified oligonucleotide.

在任一前述方法或用途中，化合物可為寡聚化合物。在任一前述方法或用途中，化合物可為單股或雙股的。在任一前述方法或用途中，化合物可靶向LRRK2。在某些實施例中，化合物包含經修飾之寡核苷酸或由其組成。在某些實施例中，化合物包含一或多種經修飾之寡核苷酸。在某些實施例中，化合物包含第一經修飾之寡核苷酸及第二經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸之長度為8至80個連接核苷、長度為10至30個連接核苷、長度為14至30個連接核苷、長度為14至23個連接核苷或長度為19至23個連接核苷。在某些實施例中，經修飾之寡核苷酸在其長度上與SEQ ID NO: 1或2中所列舉之任一核鹼基序列至少80%、至少85%、至少90%、至少95%或100%互補。在某些實施例中，經修飾之寡核苷酸包含至少一個經修飾之核苷間鍵聯、至少一個經修飾之糖及/或至少一個經修飾之核鹼基。在某些實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯。在某些實施例中，經修飾之糖為雙環糖、2’-MOE、2’-F或2’-OMe。在某些實施例中，經修飾之核鹼基為5-甲基胞嘧啶。在任一前述實施例中，每一經修飾之寡核苷酸之長度獨立地為12至30個、14至30個、14至25個、14至24個、14至23個、16至23個、17至23個、18至23個、19至23個、19至22個或19至20個連接核苷。在某些實施例中，經修飾之寡核苷酸與SEQ ID NO: 1及2之區域具有至少1個、至少2個、至少3個失配。In any of the foregoing methods or uses, the compound may be an oligomeric compound. In any of the foregoing methods or uses, the compound may be single-stranded or double-stranded. In any of the foregoing methods or uses, the compound may target LRRK2. In certain embodiments, the compound comprises or consists of a modified oligonucleotide. In certain embodiments, the compound comprises one or more modified oligonucleotides. In certain embodiments, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In certain embodiments, the modified oligonucleotide has a length of 8 to 80 linked nucleosides, a length of 10 to 30 linked nucleosides, a length of 14 to 30 linked nucleosides, a length of 14 to 23 linked nucleosides, or a length of 19 to 23 linked nucleosides. In certain embodiments, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary in length to any of the nucleobase sequences listed in SEQ ID NO: 1 or 2. In certain embodiments, the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, and/or at least one modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage. In certain embodiments, the modified sugar is a bicyclic sugar, 2'-MOE, 2'-F, or 2'-OMe. In certain embodiments, the modified nucleobase is 5-methylcytosine. In any of the foregoing embodiments, the length of each modified oligonucleotide is independently 12-30, 14-30, 14-25, 14-24, 14-23, 16-23, 17-23, 18-23, 19-23, 19-22, or 19-20 linked nucleosides. In certain embodiments, the modified oligonucleotides have at least 1, at least 2, at least 3 mismatches with regions of SEQ ID NOs: 1 and 2.

在任一前述方法或用途中，化合物包含第一及第二經修飾之寡核苷酸，其中在第一經修飾之寡核苷酸與第二經修飾之寡核苷酸之間存在互補區。在某些實施例中，第一寡核苷酸與第二寡核苷酸之間的互補區之長度為14至23個、19至23個或21至23個連接核苷。在某些實施例中，第一經修飾之寡核苷酸與第二經修飾之寡核苷酸完全互補。在某些實施例中，第一經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。在某些實施例中，第二經修飾之寡核苷酸包含至少一種選自由經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基組成之群的修飾。在某些實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或甲基膦酸酯核苷間鍵聯。在某些實施例中，經修飾之核苷間鍵聯位於第一或第二經修飾之寡核苷酸之3’末端或位於第一或第二經修飾之寡核苷酸之5’末端。在某些實施例中，第一或第二經修飾之寡核苷酸包含一或多個經修飾之糖。在某些實施例中，第一或第二經修飾之寡核苷酸之每一核苷包含經修飾之糖。在某些實施例中，經修飾之糖包含選自由鹵素、烷氧基及雙環糖組成之群的修飾。在某些實施例中，經修飾之糖包含選自由2’-MOE、2’-F及2’-OMe或其組合組成之群的修飾。在某些實施例中，第一或第二經修飾之寡核苷酸包含不超過十個2’-F糖修飾。在某些實施例中，第一或第二經修飾之寡核苷酸包含不超過五個2’-F糖修飾。In any of the foregoing methods or uses, the compound comprises a first and a second modified oligonucleotide, wherein there is a complementary region between the first modified oligonucleotide and the second modified oligonucleotide. In certain embodiments, the complementary region between the first oligonucleotide and the second oligonucleotide is 14 to 23, 19 to 23, or 21 to 23 linked nucleosides in length. In certain embodiments, the first modified oligonucleotide and the second modified oligonucleotide are completely complementary. In certain embodiments, the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the second modified oligonucleotide comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase. In certain embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage. In certain embodiments, the modified internucleoside linkage is located at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first or second modified oligonucleotide. In certain embodiments, the first or second modified oligonucleotide comprises one or more modified sugars. In certain embodiments, each nucleoside of the first or second modified oligonucleotide comprises a modified sugar. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugars. In certain embodiments, the modified sugar comprises a modification selected from the group consisting of 2'-MOE, 2'-F and 2'-OMe or a combination thereof. In certain embodiments, the first or second modified oligonucleotide comprises no more than ten 2'-F sugar modifications. In certain embodiments, the first or second modified oligonucleotide comprises no more than five 2'-F sugar modifications.

在任一前述方法或用途中，化合物包含結合基團。在某些實施例中，結合基團連接至經修飾之寡核苷酸之5’端。在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包含一或多種TrkB配位體。在某些實施例中，該一或多種TrkB配位體連接在寡核苷酸之5’端或3’端，或寡核苷酸之5’端及3’端。在某些實施例中，TrkB配位體係選自式I-式XX，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸經由磷酸二酯基連接至TrkB配位體。在某些實施例中，經修飾之寡核苷酸經由硫代磷酸酯基連接至TrkB配位體。在某些實施例中，結合基團包含一或多種脂質。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸。在某些實施例中，該一或多種脂質連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXI-式XXIV中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸包含一或多種TrkB配位體及一或多種脂質。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸。在某些實施例中，該一或多種TrkB配位體連接至經修飾之寡核苷酸之5’端。在某些實施例中，該一或多種TrkB配位體連接至經修飾之寡核苷酸之3’端。在某些實施例中，該一或多種TrkB配位體連接至經修飾之寡核苷酸之5’端及3’端。在某些實施例中，該一或多種脂質連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，該一或多種TrkB配位體係選自式I-式XX中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸，且經修飾之寡核苷酸之核苷間鍵聯係選自式XXI-式XXIV中之任一者，或其鹽、溶劑合物或水合物，其中R為經修飾之寡核苷酸。In any of the aforementioned methods or uses, the compound comprises a binding group. In certain embodiments, the binding group is linked to the 5' end of the modified oligonucleotide. In certain embodiments, the binding group is a targeting moiety. In certain embodiments, the targeting moiety comprises one or more TrkB ligands. In certain embodiments, the one or more TrkB ligands are linked to the 5' end or 3' end of the oligonucleotide, or the 5' end and 3' end of the oligonucleotide. In certain embodiments, the TrkB ligand is selected from Formula I-Formula XX, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide. In certain embodiments, the modified oligonucleotide is linked to the TrkB ligand via a phosphodiester group. In certain embodiments, the modified oligonucleotide is linked to the TrkB ligand via a thiophosphate group. In certain embodiments, the binding group comprises one or more lipids. In some embodiments, the modified oligonucleotide is a second modified oligonucleotide. In some embodiments, the one or more lipids are linked to the internucleoside linkage of the modified oligonucleotide. In some embodiments, the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXI-Formula XXIV, or a salt, solvent or hydrate thereof, wherein R is a modified oligonucleotide. In some embodiments, the modified oligonucleotide comprises one or more TrkB ligands and one or more lipids. In some embodiments, the modified oligonucleotide is a second modified oligonucleotide. In some embodiments, the one or more TrkB ligands are linked to the 5' end of the modified oligonucleotide. In some embodiments, the one or more TrkB ligands are linked to the 3' end of the modified oligonucleotide. In certain embodiments, the one or more TrkB ligands are linked to the 5' and 3' ends of the modified oligonucleotide. In certain embodiments, the one or more lipids are linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the one or more TrkB ligands are selected from any one of Formula I-XX, or a salt, solvate, or hydrate thereof, wherein R is a modified oligonucleotide, and the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXI-XXIV, or a salt, solvate, or hydrate thereof, wherein R is a modified oligonucleotide.

在任一前述方法或用途中，在某些實施例中，化合物包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₇烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₈烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₂₂烴鏈。In any of the foregoing methods or uses, in certain embodiments, the compound comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to one or more internucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C₄ -C₃₀ hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₅ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₆ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₇ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₈ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated_C22 hydrocarbon chain.

在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之末端(例如5'端及/或3'端) 10個位置內(例如8個位置內、6個位置內、5個位置內、4個位置內、3個位置內、2個位置內)的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端5個位置內的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端5個位置內的核苷之間。In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, the internucleoside linkage is between nucleosides within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of the end (e.g., the 5' end and/or the 3' end) of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkages are between nucleosides within 5 positions from the 3' end of the modified oligonucleotide.

在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的2位與3位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的2位與3位之間。In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 3' end of the modified oligonucleotide.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXI-式XXIV中之任一者。In certain embodiments, the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXI-XXIV.

在任一前述方法或用途中，在某些實施例中，化合物包含5'-膦酸酯修飾。舉例而言，在某些實施例中，經修飾之寡核苷酸包含一或多個在5'位具有膦酸酯修飾之糖。在某些實施例中，經修飾之寡核苷酸包含5'-膦酸酯修飾。在某些實施例中，經修飾之寡核苷酸包含含有5'-膦酸酯修飾之5'末端核苷(例如5'末端)。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-伸乙基膦酸酯修飾。在某些實施例中，經修飾之寡核苷酸為第一經修飾之寡核苷酸或反義寡核苷酸。In any of the foregoing methods or uses, in certain embodiments, the compound comprises a 5'-phosphonate modification. For example, in certain embodiments, the modified oligonucleotide comprises one or more sugars having a phosphonate modification at the 5' position. In certain embodiments, the modified oligonucleotide comprises a 5'-phosphonate modification. In certain embodiments, the modified oligonucleotide comprises a 5'-terminal nucleoside (e.g., the 5' end) containing a 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-ethylphosphonate modification. In certain embodiments, the modified oligonucleotide is a first modified oligonucleotide or an antisense oligonucleotide.

在任一前述方法或用途中，化合物包含選自由表3中之IA Ref ID NO中之任一者組成之群的第一經修飾之寡核苷酸及長度為14至23個連接核苷且與該第一經修飾之寡核苷酸完全互補的第二經修飾之寡核苷酸。在某些實施例中，化合物包含選自表3中之IA Ref ID NO中之任一者的第一經修飾之寡核苷酸及選自表3中之IS Ref ID NO中之任一者的第二經修飾之寡核苷酸。在某些實施例中，化合物係呈醫藥學上可接受之鹽形式。在某些實施例中，醫藥學上可接受之鹽為鈉鹽。在某些實施例中，醫藥學上可接受之鹽為鉀鹽。在某些實施例中，組合物包含如前述實施例中任一項之化合物以及醫藥學上可接受之載劑。In any of the foregoing methods or uses, the compound comprises a first modified oligonucleotide selected from the group consisting of any one of the IA Ref ID NOs in Table 3 and a second modified oligonucleotide having a length of 14 to 23 linked nucleosides and fully complementary to the first modified oligonucleotide. In certain embodiments, the compound comprises a first modified oligonucleotide selected from any one of the IA Ref ID NOs in Table 3 and a second modified oligonucleotide selected from any one of the IS Ref ID NOs in Table 3. In certain embodiments, the compound is in the form of a pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt. In certain embodiments, the composition comprises a compound as in any of the foregoing embodiments and a pharmaceutically acceptable carrier.

在任一前述方法或用途中，將化合物或包含任一前述實施例之化合物之組合物以治療有效量投與給個體。在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以足以遞送約1至100 mg/kg個體體重之劑量水準投與給個體。在某些實施例中，將化合物或包含任一前述實施例之化合物之組合物以約25 mg至約1,000 mg之固定劑量投與給個體。在某些實施例中，在一天內向個體投與一或多次組合物，直至該劑量水準或固定劑量。In any of the aforementioned methods or uses, a compound or a composition comprising a compound of any of the aforementioned embodiments is administered to a subject in a therapeutically effective amount. In certain embodiments, a compound or a composition comprising a compound of any of the aforementioned embodiments is administered to a subject at a dosage level sufficient to deliver about 1 to 100 mg/kg of the subject's body weight. In certain embodiments, a compound or a composition comprising a compound of any of the aforementioned embodiments is administered to a subject at a fixed dose of about 25 mg to about 1,000 mg. In certain embodiments, the composition is administered to a subject one or more times a day up to the dosage level or fixed dose.

在任一前述方法或用途中，每天、每週、每月、每季度或每年向個體投與化合物或包含任一前述實施例之化合物之組合物。在某些實施例中，約每季度一次(亦即每三個月一次)至約每年一次向個體投與化合物或包含任一前述實施例之化合物之組合物。在某些實施例中，約每季度一次、約每六個月一次或約每年一次向個體投與化合物或包含任一前述實施例之化合物之組合物。某些化合物In any of the foregoing methods or uses, the compound or a composition comprising a compound of any of the foregoing embodiments is administered to the subject daily, weekly, monthly, quarterly, or annually. In certain embodiments, the compound or a composition comprising a compound of any of the foregoing embodiments is administered to the subject from about once a quarter (i.e., once every three months) to about once a year. In certain embodiments, the compound or a composition comprising a compound of any of the foregoing embodiments is administered to the subject about once a quarter, about once every six months, or about once a year.Certain compounds

在某些態樣中，本揭示案係關於包含寡聚化合物或由寡聚化合物組成之化合物。在某些實施例中，寡聚化合物包含與靶核酸之核鹼基序列互補之核鹼基序列。In certain aspects, the present disclosure relates to compounds comprising or consisting of oligomeric compounds. In certain embodiments, the oligomeric compound comprises a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid.

在某些態樣中，本揭示案係關於包含經修飾之寡核苷酸或由經修飾之寡核苷酸組成之化合物。在某些實施例中，經修飾之寡核苷酸具有與靶核酸之核鹼基序列互補之核鹼基序列。In certain aspects, the present disclosure relates to compounds comprising or consisting of modified oligonucleotides. In certain embodiments, the modified oligonucleotides have a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid.

在某些態樣中，本揭示案係關於包含反義寡核苷酸或由反義寡核苷酸組成之化合物。在某些實施例中，反義寡核苷酸具有與靶核酸之核鹼基序列互補之核鹼基序列。In certain aspects, the present disclosure relates to compounds comprising or consisting of antisense oligonucleotides. In certain embodiments, the antisense oligonucleotides have a nucleobase sequence that is complementary to the nucleobase sequence of a target nucleic acid.

在某些態樣中，本揭示案係關於作為單股化合物之化合物。在某些實施例中，單股化合物包含寡聚化合物或由寡聚化合物組成。在某些實施例中，此一寡聚化合物包含寡核苷酸及視情況結合基團或由寡核苷酸及視情況結合基團組成。在某些實施例中，寡核苷酸為經修飾之寡核苷酸。在某些實施例中，寡核苷酸為反義寡核苷酸。在某些實施例中，單股化合物之寡核苷酸或經修飾之寡核苷酸包含自補核鹼基序列。In some aspects, the present disclosure relates to compounds that are single-stranded compounds. In some embodiments, the single-stranded compounds include or consist of oligomeric compounds. In some embodiments, such an oligomeric compound includes or consists of an oligonucleotide and, optionally, a binding group. In some embodiments, the oligonucleotide is a modified oligonucleotide. In some embodiments, the oligonucleotide is an antisense oligonucleotide. In some embodiments, the oligonucleotide of the single-stranded compound or the modified oligonucleotide includes a self-complementary nucleobase sequence.

在某些態樣中，本揭示案係關於作為雙股化合物之化合物。在某些實施例中，雙股化合物包含寡聚化合物或由寡聚化合物組成。在某些實施例中，雙股化合物包含第一寡核苷酸及第二寡核苷酸。在某些實施例中，第一寡核苷酸具有與靶核酸互補之區域，且第二寡核苷酸具有與第一經修飾之寡核苷酸互補之區域。在某些實施例中，雙股化合物包含經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸具有與靶核酸互補之區域。在某些實施例中，雙股化合物包含第一經修飾之寡核苷酸及第二經修飾之寡核苷酸。在某些實施例中，第一經修飾之寡核苷酸具有與靶核酸互補之區域，且第二經修飾之寡核苷酸具有與第一經修飾之寡核苷酸互補之區域。在某些實施例中，雙股化合物之寡核苷酸或經修飾之寡核苷酸為RNA寡核苷酸。在此等實施例中，經修飾之寡核苷酸中之胸腺嘧啶核鹼基經尿嘧啶核鹼基置換。In some aspects, the disclosure relates to compounds that are double-stranded compounds. In some embodiments, the double-stranded compound comprises or consists of an oligomeric compound. In some embodiments, the double-stranded compound comprises a first oligonucleotide and a second oligonucleotide. In some embodiments, the first oligonucleotide has a region that is complementary to the target nucleic acid, and the second oligonucleotide has a region that is complementary to the first modified oligonucleotide. In some embodiments, the double-stranded compound comprises a modified oligonucleotide. In some embodiments, the modified oligonucleotide has a region that is complementary to the target nucleic acid. In some embodiments, the double-stranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In some embodiments, the first modified oligonucleotide has a region that is complementary to the target nucleic acid, and the second modified oligonucleotide has a region that is complementary to the first modified oligonucleotide. In certain embodiments, the double-stranded oligonucleotide or modified oligonucleotide is an RNA oligonucleotide. In these embodiments, the thymine nucleobase in the modified oligonucleotide is replaced by a uracil nucleobase.

在某些實施例中，本文所闡述之化合物包含結合基團。在某些實施例中，雙股化合物之第一寡核苷酸或第一經修飾之寡核苷酸包含結合基團。在某些實施例中，雙股化合物之第二寡核苷酸或第二經修飾之寡核苷酸包含結合基團。在某些實施例中，雙股化合物之第一寡核苷酸或第一經修飾之寡核苷酸以及第二寡核苷酸或第二經修飾之寡核苷酸各自包含結合基團。In certain embodiments, the compounds described herein comprise a binding group. In certain embodiments, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound comprises a binding group. In certain embodiments, the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound comprises a binding group. In certain embodiments, the first oligonucleotide or the first modified oligonucleotide and the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound each comprise a binding group.

在某些實施例中，化合物之長度為14-30個連接核苷。在某些實施例中，雙股化合物之第一寡核苷酸或第一經修飾之寡核苷酸之長度為14-30個連接核苷。在某些實施例中，第二寡核苷酸或第二經修飾之寡核苷酸之長度為14-30個連接核苷。在某些實施例中，雙股化合物之寡核苷酸或經修飾之寡核苷酸在該化合物之一端或兩端為平端。在某些實施例中，雙股化合物之寡核苷酸或經修飾之寡核苷酸在該化合物之一端或兩端包括非互補懸突核苷。In some embodiments, the length of the compound is 14-30 linked nucleosides. In some embodiments, the length of the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound is 14-30 linked nucleosides. In some embodiments, the length of the second oligonucleotide or the second modified oligonucleotide is 14-30 linked nucleosides. In some embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound is blunt-ended at one or both ends of the compound. In some embodiments, the oligonucleotide or the modified oligonucleotide of the double-stranded compound includes non-complementary overhanging nucleosides at one or both ends of the compound.

在某些實施例中，化合物具有包含SEQ ID NO: 11-44及83-89中之任一者之至少14個鄰接核鹼基之核鹼基序列。在某些實施例中，雙股化合物之寡核苷酸或經修飾之寡核苷酸中之一者具有包含SEQ ID NO: 11-44及83-89中之任一者之至少14個鄰接核鹼基之核鹼基序列。In certain embodiments, the compound has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, one of the oligonucleotides or modified oligonucleotides of the double-stranded compound has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 11-44 and 83-89.

單股及雙股化合物之實例包括(但不限於)寡核苷酸、反義寡核苷酸、siRNA、靶向微小RNA之寡核苷酸、基於佔位之化合物(例如mRNA加工或轉譯阻斷化合物及剪接化合物)及單股RNAi化合物(例如小髮夾RNA (shRNA)、單股siRNA (ssRNA)及微小RNA模擬物)。Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNAs, oligonucleotides targeting microRNAs, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and single-stranded RNAi compounds (e.g., small hairpin RNA (shRNA), single-stranded siRNA (ssRNA), and microRNA mimetics).

在某些實施例中，本文所闡述之化合物具有核鹼基序列，當該核鹼基序列以5’至3’方向書寫時，包含該序列所靶向之靶核酸之靶區域的反向互補序列。In certain embodiments, the compounds described herein have a nucleobase sequence that, when written in the 5' to 3' direction, comprises the reverse complement of a target region of a target nucleic acid to which the sequence is targeted.

在某些實施例中，本文所闡述之化合物包含長度為12至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為12至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為14至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為14至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為15至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為15至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為16至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為16至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為17至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為17至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為18至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為18至23個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為19至30個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為19至23個連接亞單元之寡核苷酸。換言之，此等寡核苷酸分別為12至30個連接亞單元、12至23個連接亞單元、14至30個連接亞單元、14至23個連接亞單元、15至30個連接亞單元、15至23個連接亞單元、16至30個連接亞單元、16至23個連接亞單元、17至30個連接亞單元、17至23個連接亞單元、18至30個連接亞單元、18至23個連接亞單元、19至30個連接亞單元或19至23個連接亞單元。在某些實施例中，本文所闡述之化合物包含長度為14個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為16個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為17個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為18個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為19個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為20個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為21個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為22個連接亞單元之寡核苷酸。在某些實施例中，本文所闡述之化合物包含長度為23個連接亞單元之寡核苷酸。在其他實施例中，本文所闡述之化合物包含8至80個、12至50個、13至30個、13至50個、14至30個、14至50個、15至30個、15至50個、16至30個、16至50個、17至30個、17至50個、18至23個、18至24個、18至25個、18至50個、19至23個、19至30個、19至50個、20至23個或20至30個連接亞單元之寡核苷酸。在某些此類實施例中，本文所闡述之化合物包含長度為8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個連接亞單元或由上述值中之任兩者所界定範圍之寡核苷酸。In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 12 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 12 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 14 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 14 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 15 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 15 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 16 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 16 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 17 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 17 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 18 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 18 to 23 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 19 to 30 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 19 to 23 linked subunits. In other words, these oligonucleotides are 12 to 30 linked subunits, 12 to 23 linked subunits, 14 to 30 linked subunits, 14 to 23 linked subunits, 15 to 30 linked subunits, 15 to 23 linked subunits, 16 to 30 linked subunits, 16 to 23 linked subunits, 17 to 30 linked subunits, 17 to 23 linked subunits, 18 to 30 linked subunits, 18 to 23 linked subunits, 19 to 30 linked subunits, or 19 to 23 linked subunits, respectively. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 14 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 16 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 17 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 18 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 19 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 20 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 21 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 22 linked subunits. In certain embodiments, the compounds described herein comprise oligonucleotides having a length of 23 linked subunits. In other embodiments, the compounds described herein comprise 8-80, 12-50, 13-30, 13-50, 14-30, 14-50, 15-30, 15-50, 16-30, 16-50, 17-30, 17-50, 18-23, 18-24, 18-25, 18-50, 19-23, 19-30, 19-50, 20-23, or 20-30 oligonucleotides linked to subunits. In certain such embodiments, the compounds described herein comprise an oligonucleotide having a length of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 linked subunits, or a range defined by any two of the above values.

在某些實施例中，化合物可進一步包含額外部分，諸如結合基團或遞送部分。在某些實施例中，此等化合物為寡聚化合物，且額外部分連接至寡核苷酸。在某些實施例中，結合基團連接至寡核苷酸之核苷。In some embodiments, the compound may further comprise an additional moiety, such as a binding group or a delivery moiety. In some embodiments, these compounds are oligomeric compounds, and the additional moiety is linked to an oligonucleotide. In some embodiments, the binding group is linked to the nucleoside of the oligonucleotide.

在某些實施例中，化合物可縮短或截短。舉例而言，可自寡核苷酸之5’端(5’截短)或替代地3’端(3’截短)缺失一或多個亞單元。In certain embodiments, the compound may be shortened or truncated. For example, one or more subunits may be deleted from the 5' end (5' truncation) or alternatively the 3' end (3' truncation) of the oligonucleotide.

在某些實施例中，化合物可加長。舉例而言，一或多個亞單元可連接至寡核苷酸之3'端或5'端。在某些實施例中，至少一個亞單元(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50或更多個亞單元)連接至寡核苷酸之5'端。在某些實施例中，至少一個亞單元(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50或更多個亞單元)連接至寡核苷酸之3'端。在某些實施例中，至少一或多個亞單元可連接至雙股化合物之寡核苷酸之3'端或5'端，從而產生3'端及/或5'端懸突。在某些實施例中，至少一個亞單元(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50或更多個亞單元)連接至雙股化合物之兩種寡核苷酸之5'端。在某些實施例中，至少一個亞單元(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50或更多個亞單元)連接至雙股化合物之兩種寡核苷酸之3'端。在某些實施例中，亞單元連接至雙股化合物之兩種寡核苷酸之同一端(例如，亞單元連接至一種寡核苷酸之3'端，且亞單元連接至另一寡核苷酸之5'端)。在某些實施例中，當亞單元連接至雙股化合物之兩種寡核苷酸之同一端時，連接至每一寡核苷酸之亞單元數量可相同或可不同。在某些實施例中，當亞單元連接至雙股化合物之兩種寡核苷酸之同一端時，連接至每一寡核苷酸之亞單元數量係相同的。在某些實施例中，當亞單元連接至雙股化合物之兩種寡核苷酸之同一端時，連接至每一寡核苷酸之亞單元數量係不同的。亞單元連接至雙股化合物之兩種寡核苷酸之同一端的此種情形可發生在雙股化合物之一端或兩端。在某些實施例中，連接至3'端及/或5'端之亞單元經修飾。In some embodiments, the compound can be elongated. For example, one or more subunits can be attached to the 3' end or the 5' end of the oligonucleotide. In some embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 5' end of the oligonucleotide. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 3' end of the oligonucleotide. In certain embodiments, at least one or more subunits may be attached to the 3' end or 5' end of the oligonucleotide of the double-stranded compound, thereby generating a 3' and/or 5' overhang. In certain embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is linked to the 5' end of both oligonucleotides of the double-stranded compound. In some embodiments, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is linked to the 3' end of both oligonucleotides of the double-stranded compound. In some embodiments, the subunits are linked to the same end of both oligonucleotides of the double-stranded compound (e.g., the subunit is linked to the 3' end of one oligonucleotide and the subunit is linked to the 5' end of the other oligonucleotide). In some embodiments, when a subunit is connected to the same end of two oligonucleotides of a double-stranded compound, the number of subunits connected to each oligonucleotide may be the same or different. In some embodiments, when a subunit is connected to the same end of two oligonucleotides of a double-stranded compound, the number of subunits connected to each oligonucleotide is the same. In some embodiments, when a subunit is connected to the same end of two oligonucleotides of a double-stranded compound, the number of subunits connected to each oligonucleotide is different. This situation where a subunit is connected to the same end of two oligonucleotides of a double-stranded compound can occur at one end or both ends of the double-stranded compound. In some embodiments, the subunits connected to the 3' end and/or the 5' end are modified.

在某些實施例中，本文所闡述之化合物為寡核苷酸。在某些實施例中，本文所闡述之化合物為經修飾之寡核苷酸。在某些實施例中，本文所闡述之化合物為反義寡核苷酸。在某些實施例中，本文所闡述之化合物為寡聚化合物。在某些實施例中，本文所闡述之化合物為RNAi化合物。在某些實施例中，本文所闡述之化合物為siRNA化合物。In certain embodiments, the compounds described herein are oligonucleotides. In certain embodiments, the compounds described herein are modified oligonucleotides. In certain embodiments, the compounds described herein are antisense oligonucleotides. In certain embodiments, the compounds described herein are oligomeric compounds. In certain embodiments, the compounds described herein are RNAi compounds. In certain embodiments, the compounds described herein are siRNA compounds.

在某些實施例中，本文所闡述之化合物可包含本文所闡述之靶向LRRK2之寡核苷酸序列中之任一者。在某些實施例中，化合物可為雙股的。In certain embodiments, the compounds described herein may comprise any of the oligonucleotide sequences targeting LRRK2 described herein. In certain embodiments, the compound may be double-stranded.

在某些實施例中，化合物包含寡核苷酸，該寡核苷酸包含SEQ ID NO: 11-44及83-89中之任一者之至少8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23個鄰接核鹼基之部分。在某些實施例中，化合物包含寡核苷酸，該寡核苷酸包含SEQ ID NO: 11-44及83-89中之任一者之至少8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23個鄰接核鹼基之部分。在某些實施例中，化合物包含第二寡核苷酸。在某些實施例中，化合物包含寡核苷酸，該寡核苷酸包含SEQ ID NO: 45-82及90-96中之任一者之至少8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23個鄰接核鹼基之部分。In certain embodiments, the compound comprises an oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 adjacent nucleobases of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises an oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 adjacent nucleobases of any one of SEQ ID NOs: 11-44 and 83-89. In certain embodiments, the compound comprises a second oligonucleotide. In certain embodiments, the compound comprises an oligonucleotide comprising a portion of at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous nucleobases of any one of SEQ ID NOs: 45-82 and 90-96.

在某些實施例中，化合物包含核糖核苷酸，對於本文所提供之任一序列，該等核糖核苷酸中之寡核苷酸用尿嘧啶(U)代替胸腺嘧啶(T)。在某些實施例中，化合物包含去氧核糖核苷酸，對於本文所提供之任一序列，該等去氧核糖核苷酸中之寡核苷酸用胸腺嘧啶(T)代替尿嘧啶(U)。某些機制In certain embodiments, the compounds comprise ribonucleotides in which oligonucleotides substitute uracil (U) for thymine (T) for any of the sequences provided herein. In certain embodiments, the compounds comprise deoxyribonucleotides in which oligonucleotides substitute thymine (T) for uracil (U) for any of the sequences provided herein.Certain mechanisms

在某些實施例中，本文所闡述之化合物包含經修飾之寡核苷酸或由經修飾之寡核苷酸組成。在某些實施例中，本文所闡述之化合物包含反義寡核苷酸或由反義寡核苷酸組成。在某些實施例中，化合物包含寡聚化合物或由寡聚化合物組成。在某些實施例中，本文所闡述之化合物能夠與靶核酸雜交。在某些實施例中，本文所闡述之化合物選擇性地影響一或多種靶核酸。此等化合物包含如下核鹼基序列，該核鹼基序列與一或多種靶核酸雜交，從而產生一或多種期望活性，且不與一或多種非靶核酸雜交或與一或多種非靶核酸雜交之方式不會產生顯著不期望之活性。In certain embodiments, the compounds described herein comprise modified oligonucleotides or consist of modified oligonucleotides. In certain embodiments, the compounds described herein comprise antisense oligonucleotides or consist of antisense oligonucleotides. In certain embodiments, the compounds described herein comprise oligomeric compounds or consist of oligomeric compounds. In certain embodiments, the compounds described herein are capable of hybridizing with target nucleic acids. In certain embodiments, the compounds described herein selectively affect one or more target nucleic acids. These compounds comprise a nucleobase sequence that hybridizes with one or more target nucleic acids to produce one or more desired activities, and does not hybridize with one or more non-target nucleic acids or hybridizes with one or more non-target nucleic acids in a manner that does not produce significant undesirable activities.

在某些實施例中，本文所闡述之化合物與靶核酸雜交募集一或多種使靶核酸裂解之蛋白質。舉例而言，本文所闡述之某些化合物或該化合物之一部分裝載至RNA誘導之沈默複合物(RISC)中，最終導致靶核酸裂解。舉例而言，本文所闡述之某些化合物導致靶核酸由亞古爾蛋白(Argonaute)裂解。裝載至RISC中之化合物為RNAi化合物。RNAi化合物可為雙股(siRNA)或單股(ssRNA)。In certain embodiments, the compounds described herein hybridize with a target nucleic acid to recruit one or more proteins that cleave the target nucleic acid. For example, certain compounds described herein or a portion of the compounds are loaded into the RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain compounds described herein cause cleavage of the target nucleic acid by Argonaute. The compound loaded into RISC is an RNAi compound. The RNAi compound can be double-stranded (siRNA) or single-stranded (ssRNA).

在某些實施例中，本文所闡述之化合物與靶核酸雜交不募集裂解該靶核酸之蛋白質。在某些此類實施例中，化合物與靶核酸雜交改變該靶核酸之剪接。在某些實施例中，化合物與靶核酸雜交抑制該靶核酸與蛋白質或其他核酸之間的結合相互作用。在某些此類實施例中，化合物與靶核酸雜交改變RNA加工。在某些此類實施例中，化合物與靶核酸雜交改變該靶核酸之轉譯。In certain embodiments, the compounds described herein hybridize with target nucleic acids without recruiting proteins that cleave the target nucleic acids. In certain such embodiments, the compounds hybridize with target nucleic acids to alter the splicing of the target nucleic acids. In certain embodiments, the compounds hybridize with target nucleic acids to inhibit binding interactions between the target nucleic acids and proteins or other nucleic acids. In certain such embodiments, the compounds hybridize with target nucleic acids to alter RNA processing. In certain such embodiments, the compounds hybridize with target nucleic acids to alter the translation of the target nucleic acids.

可直接或間接觀察到化合物與靶核酸雜交所產生之活性。在某些實施例中，觀察或偵測活性涉及觀察或偵測靶核酸或由該靶核酸編碼的蛋白質之量的變化、核酸或蛋白質之剪接變異體之比率的變化及/或細胞或動物之表型變化。某些修飾The activity resulting from the hybridization of the compound with the target nucleic acid can be observed directly or indirectly. In certain embodiments, observing or detecting the activity involves observing or detecting a change in the amount of the target nucleic acid or a protein encoded by the target nucleic acid, a change in the ratio of splicing variants of the nucleic acid or protein, and/or a phenotypic change in a cell or animal.Certain modifications

在某些態樣中，本揭示案係關於包含寡核苷酸或由寡核苷酸組成之化合物。寡核苷酸係由連接核苷組成。在某些實施例中，寡核苷酸可為未經修飾之RNA或DNA，或可經修飾。在某些實施例中，寡核苷酸為經修飾之寡核苷酸。在某些實施例中，相對於未經修飾之RNA或DNA，經修飾之寡核苷酸包含至少一個經修飾之糖、經修飾之核鹼基或經修飾之核苷間鍵聯。在某些實施例中，寡核苷酸具有經修飾之核苷。經修飾之核苷可包含經修飾之糖、經修飾之核鹼基或經修飾之糖及經修飾之核鹼基二者。經修飾之寡核苷酸亦可包括末端修飾，例如5’端修飾及3’端修飾。糖修飾及模體In some aspects, the present disclosure relates to compounds comprising or consisting of oligonucleotides. Oligonucleotides are composed of linked nucleosides. In some embodiments, the oligonucleotide can be unmodified RNA or DNA, or can be modified. In some embodiments, the oligonucleotide is a modified oligonucleotide. In some embodiments, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified internucleoside linkage relative to unmodified RNA or DNA. In some embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside may comprise a modified sugar, a modified nucleobase, or both a modified sugar and a modified nucleobase. The modified oligonucleotide may also include terminal modifications, such as a 5' end modification and a 3' end modification.Sugar modifications and motifs

在某些實施例中，經修飾之糖為經取代之呋喃糖基糖或經修飾之非雙環糖。在某些實施例中，經修飾之糖為經修飾之雙環或三環糖。在某些實施例中，經修飾之糖為糖替代物。糖替代物可包含本文所闡述之一或多種取代。In certain embodiments, the modified sugar is a substituted furanosyl sugar or a modified non-bicyclic sugar. In certain embodiments, the modified sugar is a modified bicyclic or tricyclic sugar. In certain embodiments, the modified sugar is a sugar surrogate. The sugar surrogate may comprise one or more substitutions described herein.

在某些實施例中，經修飾之糖為經取代之呋喃糖基糖或經修飾之非雙環糖。在某些實施例中，呋喃糖基糖為核糖基糖。在某些實施例中，呋喃糖基糖包含一或多個取代基，包括(但不限於)在2’位、3’位、4’位及5’位之取代基。In some embodiments, the modified sugar is a substituted furanosyl sugar or a modified non-bicyclic sugar. In some embodiments, the furanosyl sugar is a ribosyl sugar. In some embodiments, the furanosyl sugar comprises one or more substituents, including but not limited to substituents at the 2' position, 3' position, 4' position, and 5' position.

在某些實施例中，2’位取代基包括(但不限於) F及OCH₃(「OMe」、「O-甲基」或「甲氧基」)。在某些實施例中，適於經修飾之非雙環糖之2’位取代基包括(但不限於)鹵基、烯丙基、胺基、疊氮基、SH、CN、OCN、CF₃、OCF₃、F、Cl、Br、SCH₃、SOCH₃、SO₂CH₃、ONO₂、NO₂、N₃及NH₂。在某些實施例中，2’位取代基包括(但不限於) O-(C₁-C₁₀)烷氧基、烷氧基烷基、O-烷基、S-烷基、N-烷基、O-烯基、S-烯基、N-烯基、O-炔基、S-炔基、N-炔基、O-烷基-O-烷基、炔基，其中烷基、烯基及炔基可為經取代或未經取代之C₁至C₁₀烷基或C₂至C₁₀烯基及炔基。在某些實施例中，2’位取代基包括(但不限於)烷芳基、芳烷基、O-烷芳基及O-芳烷基。在某些實施例中，該等2’取代基可進一步經一或多個獨立地選自以下之取代基取代：羥基、烷氧基、羧基、苯甲基、苯基、硝基(NO₂)、硫醇、硫烷氧基、硫代烷基、鹵素、烷基、芳基、烯基及炔基。在某些實施例中，2’位取代基包括(但不限於) O[(CH₂)_nO]_mCH₃、O(CH₂)_nOCH₃、O(CH₂)_nCH₃、O(CH2)_nONH₂、O(CH₂)_nNH₂、O(CH₂)_nSCH₃及O(CH₂)_nON[(CH₂)_nCH₃)]₂，其中n及m獨立地為1至約10。在某些實施例中，2’位取代基包括(但不限於) OCH₂CH₂OCH₃(「MOE」)、O(CH₂)₂ON(CH₃)₂(「DMAOE」)、O(CH₂)₂O(CH₂)₂N(CH₃)₂(「DMAEOE」)及OCH₂C(=O)-N(H)CH₃(「NMA」)。In some embodiments, 2'-position substituents include, but are not limited to, F and OCH₃ ("OMe", "O-methyl" or "methoxy"). In some embodiments, 2'-position substituents suitable for modified non-bicyclic sugars include, but are not limited to, halogen, allyl, amine, azido, SH, CN, OCN, CF₃ , OCF₃ , F, Cl, Br, SCH₃ , SOCH₃ , SO₂ CH₃ , ONO₂ , NO₂ , N₃ and NH₂ . In some embodiments, the 2'-substituent includes, but is not limited to, O-(C₁ -C₁₀ ) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, alkynyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C₁ to C₁₀ alkyl or C₂ to C₁₀ alkenyl and alkynyl. In some embodiments, the 2'-substituent includes, but is not limited to, alkaryl, aralkyl, O-alkaryl and O-aralkyl. In certain embodiments, the 2' substituents may be further substituted with one or more substituents independently selected from the group consisting of hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro(_NO2 ), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the₂ ' substituents include, but are not limited to, O[(_CH2 )_nO ]_mCH3 , O(_CH2 )_nOCH3 , O(CH2)_nCH3 , O(_CH2 )_nONH2 , O_(CH2 )_nNH2 , O(_CH2 )_nSCH3 , and O(_CH2 )_nON[ (_CH2 )_nCH3 )_]2,whereinn and m are independently 1 to about 10. In certain embodiments, the 2'-position substituent_includes , but is not limited to,_OCH2CH2OCH3 ("MOE"), O(_CH2 )_2ON (_CH3 )₂ ("DMAOE_" ), O(_CH2 )_2O (_CH2 )_2N (_CH3 )₂ ("DMAEOE"), and_OCH2C (=O)-N(H)_CH3 ("NMA").

在某些實施例中，適於經修飾之非雙環糖之4’位取代基包括(但不限於)烷氧基(例如甲氧基)、烷基及Manoharan等人，WO 2015/106128中所闡述之彼等取代基。在某些實施例中，適於經修飾之非雙環糖之5’位取代基包括(但不限於)甲基(「Me」或「CH3」) (R或S)、乙烯基及甲氧基。在某些實施例中，5'修飾為5'-單磷酸酯((HO)₂(O)P-O-5')；5'-二磷酸酯((HO)₂(O)P-O-P(HO)(O)-O-5')；5'-三磷酸酯((HO)₂(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5')；5'-鳥苷帽(7-甲基化或非甲基化) (7m-G-O-5'-(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5')；5'腺苷帽(Appp)，及任何經修飾或未經修飾之核苷酸帽結構(N-O-5'(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5')；5'-單硫代磷酸酯(硫代磷酸酯；(HO)₂(S)P-O-5')；5'-單二硫代磷酸酯(二硫代磷酸酯；(HO)(HS)(S)P-O-5')、5'硫代磷酸酯((HO)₂(O)P-S-5')；氧/硫置換之單磷酸酯、二磷酸酯及三磷酸酯之任何額外組合(例如5'-α-硫基三磷酸酯、5'-γ硫基三磷酸酯等)、5'-胺基磷酸酯((HO)₂(O)P-NH-5'、(HO)(NH₂)(O)P-O-5')、5'烷基膦酸酯(R=烷基=甲基、乙基、異丙基、丙基等，例如RP(OH)(O)-O-5'-)、5'烯基膦酸酯(亦即乙烯基、經取代之乙烯基)、(OH)₂(O)P-5'-CH₂-)、5'烷基醚膦酸酯(R=烷基醚=甲氧基甲基(MeOCH₂-)、乙氧基甲基等，例如RP(OH)(O)-O-5'-)。在某些實施例中，一或多個糖包含5'-膦酸酯修飾。在某些實施例中，5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。在某些實施例中，一或多個糖包含5'-乙烯基膦酸酯修飾。在某些實施例中，一或多個糖包含5'-伸乙基膦酸酯修飾。在某些實施例中，5'修飾位於寡核苷酸之末端。在某些實施例中，5'修飾位於反義寡核苷酸之末端。 在某些實施例中，可將本文所闡述之2’位、4’位及5’位取代基添加至糖上之其他特定位置。在某些實施例中，此類取代基可添加至3’末端核苷上之糖的3’位或5’末端核苷之5’位。在某些實施例中，經修飾之非雙環糖可包含一個以上之非橋接糖取代基。在某些此類實施例中，經修飾之非雙環糖取代基包括(但不限於) 5’-Me-2’-F、5’-Me-2’-OMe (包括R及S異構物二者)。在某些實施例中，經修飾之糖取代基包括Migawa等人，WO 2008/101157及Rajeev等人，US2013/0203836中所闡述之彼等取代基。In certain embodiments, suitable 4'-position substituents for modified non-bicyclic sugars include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128. In certain embodiments, suitable 5'-position substituents for modified non-bicyclic sugars include, but are not limited to, methyl ("Me" or "CH3") (R or S), vinyl, and methoxy. In certain embodiments, the 5' modification is 5'-monophosphate ((HO)₂ (O)PO-5');5'-diphosphate ((HO)₂ (O)POP(HO)(O)-O-5');5'-triphosphate ((HO)₂ (O)PO-(HO)(O)POP(HO)(O)-O-5');5'-guanosine cap (7-methylated or unmethylated) (7m-GO-5'-(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5');5' adenosine cap (Appp), and any modified or unmodified nucleotide cap structure (NO-5'(HO)(O)PO-(HO)(O)POP(HO)(O)-O-5');5'-monothioate(phosphorothioate; (HO)₂ any additional combinations of oxygen/sulfur substituted monophosphates, diphosphates, and triphosphates (e.g., 5'-α-thiotriphosphate, 5'-γ-thiotriphosphate, etc.), 5'-phosphamidates ((HO)₂ (O)P-NH-5', (HO)(NH₂ )(O)PO-5'), 5'alkylphosphonates (R=alkyl=methyl, ethyl, isopropyl, propyl, etc., e.g., RP(OH)(O)-O-_5'- ), 5'alkenylphosphonates (i.e., vinyl, substituted vinyl), (OH)₂ (O)P-5'-CH₂ -), 5'alkyletherphosphonates (R=alkylether=methoxymethyl (MeOCH₂ -), ethoxymethyl, etc., such as RP(OH)(O)-O-5'-). In certain embodiments, one or more sugars comprise a 5'-phosphonate modification. In certain embodiments, the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-vinylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-ethylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-vinylphosphonate modification. In certain embodiments, one or more sugars comprise a 5'-ethylphosphonate modification. In certain embodiments, the 5' modification is located at the end of the oligonucleotide. In certain embodiments, the 5' modification is located at the end of the antisense oligonucleotide. In certain embodiments, the 2', 4', and 5' substituents described herein may be added to other specific positions on the sugar. In certain embodiments, such substituents may be added to the 3' position of the sugar on the 3' terminal nucleoside or the 5' position of the 5' terminal nucleoside. In certain embodiments, the modified non-bicyclic sugar may include more than one non-bridging sugar substituent. In certain such embodiments, the modified non-bicyclic sugar substituent includes, but is not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, the modified sugar substituent includes those described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836.

在某些實施例中，經修飾之糖為雙環糖。雙環糖係包含兩個環之經修飾之糖，其中經由連結第一環中的兩個原子之橋形成第二環，藉此形成雙環結構。在某些實施例中，雙環糖包含橋接取代基，該橋接取代基橋接呋喃糖基環之兩個原子以形成第二環。在某些實施例中，雙環糖不包含呋喃糖基部分。「雙環核苷」(「BNA」)係具有雙環糖之核苷。在某些實施例中，雙環糖在4’與2’呋喃糖環原子之間包含橋。在某些實施例中，雙環糖在5’與3’呋喃糖環原子之間包含橋。在某些此類實施例中，呋喃糖環為核糖環。在某些實施例中，4’至2’橋接取代基包括(但不限於) 4'-CH₂-2'、4'-(CH₂)₂-2'、4'- (CH₂)₃-2'、4'-CH₂-O-2' (「LNA」)、4'-CH₂-S-2'、4'-(CH₂)₂-O-2' (「ENA」)、4'-CH(CH₃)-O-2' (當呈S構形時，為「約束乙基」或「cEt」)、4’-CH2-O-CH₂-2’、4’-CH₂-N(R)-2’、4'- CH(CH₂OCH₃)-O-2' (「約束MOE」或「cMOE」)及其類似物(例如美國專利第7,399,845號)、4'-C(CH₃)(CH₃)-O-2'及其類似物(例如美國專利第8,278,283號)、4'-CH₂-N(OCH₃)-2'及其類似物(例如美國專利第8,278,425號)、4'-CH₂-O-N(CH₃)-2' (例如美國專利公開案第2004/0171570號)、4'-CH₂-N(R)-O-2' (其中R為H、C₁-C₁₂烷基或保護基團(例如美國專利第7,427,672號))、4'-CH₂-C(H)(CH₃)-2' (例如Chattopadhyaya等人，J. Org. Chem., 2009, 74, 118- 134)及4'-CH₂-C(=CH₂)-2'及其類似物(例如美國專利第8,278,426號)。前述文獻各自之全部內容在此係以引用的方式併入本文中。教示雙環核酸核苷酸之製備之其他代表性美國專利及美國專利公開案包括(但不限於)以下：美國專利第6,268,490號；第6,525,191號；第6,670,461號；第6,770,748號；第6,794,499號；第6,998,484號；第7,053,207號；第7,034,133號；第7,084,125號；第7,399,845號；第7,427,672號；第7,569,686號；第7,741,457號；第8,022,193號；第8,030,467號；第8,278,425號；第8,278,426號；第8,278,283號；US 2008/0039618；及US 2009/0012281、US 2013/0190383；及WO 2013/036868，其各自之全部內容在此係以引用的方式併入本文中。前述雙環核苷中之任一者均可製備成具有一或多種立體化學糖構形，包括例如α-L-呋喃核糖及β-D-呋喃核糖(例如，參見WO 99/14226)。除非另有指定，否則本文指定之雙環核苷係呈β-D構形。In certain embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed by a bridge connecting two atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, the bicyclic sugar comprises a bridging substituent that bridges two atoms of the furanosyl ring to form the second ring. In certain embodiments, the bicyclic sugar does not comprise a furanosyl moiety. A "bicyclic nucleoside"("BNA") is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a bridge between the 4' and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar comprises a bridge between the 5' and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, the 4' to 2' bridging substituent includes, but is not limited to, 4'-_CH2-2 ', 4'-(_CH2 )_2-2 ', 4'-(_CH2 )3-2',_4' -CH2-_O -2'("LNA"),4'-CH2-S-2',4'-(CH2)₂ -O-2'("ENA"),4'-CH(_CH3 )_-O -2'("constrainedethyl" or "cEt" when in the S configuration), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(_CH2OCH3 )_-O -₂ '("constrainedMOE" or "cMOE_" ) and the like (e.g., U.S. Patent No. 7,399,845), 4'-C(_CH3 )-O-2'("constrainedethyl" or "cEt"), and the like (e.g., U.S. Patent No. 7,399,845), and 4'-CH2-S-₂ '. )(CH₃ )-O-2′ and its analogs (e.g., U.S. Patent No. 8,278,283), 4′-CH₂ -N(OCH₃ )-2′ and its analogs (e.g., U.S. Patent No. 8,278,425), 4′-CH₂ -ON(CH₃ )-2′ (e.g., U.S. Patent Publication No. 2004/0171570), 4′-CH₂ -N(R)-O-2′ (wherein R is H, C₁ -C₁₂ alkyl or a protecting group (e.g., U.S. Patent No. 7,427,672)), 4′-CH₂ -C(H)(CH₃ )-2′ (e.g., Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118- 134) and 4′-CH₂ -C(═CH₂ )-2' and its analogs (e.g., U.S. Patent No. 8,278,426). The entire contents of each of the foregoing documents are hereby incorporated by reference. Other representative U.S. patents and U.S. patent publications that teach the preparation of bicyclic nucleic acid nucleotides include (but are not limited to) the following: U.S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7 ,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008/0039618; and US 2009/0012281, US 2013/0190383; and WO 2013/036868, the entire contents of each of which are hereby incorporated by reference into this document. Any of the foregoing bicyclic nucleosides can be prepared with one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, for example, WO 99/14226). Unless otherwise specified, the bicyclic nucleosides specified herein are in the β-D configuration.

在某些實施例中，經修飾之糖為糖替代物。在某些實施例中，糖替代物之氧原子經例如硫、碳或氮原子置換。在某些此類實施例中，糖替代物亦可包含如本文所闡述之橋接及/或非橋接取代基。在某些實施例中，糖替代物包含具有不為5個原子之環。在某些此類實施例中，糖替代物包含環丁基部分代替呋喃戊糖基糖。在某些實施例中，糖替代物包含六員環代替呋喃戊糖基糖。在某些實施例中，糖替代物包含四氫哌喃(「THP」)代替呋喃戊糖基糖。在某些實施例中，糖替代物包含嗎啉基代替呋喃戊糖基糖。教示此等經修飾之糖結構之製備之代表性美國專利包括(但不限於)美國專利第4,981,957號；第5,118,800號；第5,166,315號；第5,185,444號；第5,319,080號；第5,359,044號；第5,393,878號；第5,446,137號；第5,466,786號；第5,514,785號；第5,519,134號；第5,567,811號；第5,576,427號；第5,591,722號；第5,597,909號；第5,610,300號；第5,627,053號；第5,639,873號；第5,646,265號；第5,658,873號；第5,670,633號；第5,700,920號；第7,875,733號；第7,939,677號、第8,088,904號；第8,440,803號；及第9,005,906號，前述專利各自之全部內容在此係以引用的方式併入本文中。In certain embodiments, the modified sugar is a sugar substitute. In certain embodiments, the oxygen atom of the sugar substitute is replaced by, for example, a sulfur, carbon or nitrogen atom. In certain such embodiments, the sugar substitute may also include bridging and/or non-bridging substituents as described herein. In certain embodiments, the sugar substitute includes a ring having not 5 atoms. In certain such embodiments, the sugar substitute includes a cyclobutyl moiety replacing a furanopentosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring replacing a furanopentosyl sugar. In certain embodiments, the sugar substitute includes tetrahydropyran ("THP") replacing a furanopentosyl sugar. In certain embodiments, the sugar substitute includes a morpholinyl group replacing a furanopentosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Patent Nos. 4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5 ,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677; 8,088,904; 8,440,803; and 9,005,906, the entire contents of each of the foregoing patents are hereby incorporated by reference into this article.

在一些實施例中，糖替代物包含非環狀部分。在某些實施例中，糖替代物為解鎖核酸(「UNA」)。UNA係一種解鎖非環狀核酸，其中糖之任何鍵均已去除，從而形成解鎖「糖」殘基。在一個實例中，UNA亦涵蓋C1’-C4’之間的鍵(亦即C1’碳與C4’碳之間的共價碳-氧-碳鍵)已去除之單體。在另一實例中，糖之C2’-C3’鍵(亦即C2’碳與C3’碳之間的共價碳-碳鍵)已去除。教示UNA之製備之代表性美國公開案包括(但不限於)美國專利第8,314,227號；及美國專利公開案第2013/0096289號；第2013/0011922號；及第2011/0313020號，其各自之全部內容在此係以引用的方式併入本文中。在某些實施例中，糖替代物包含肽核酸(「PNA」)、非環狀丁基核酸(例如，參見Kumar等人，Org. Biomol. Chem., 2013, 11, 5853-5865)，以及Manoharan等人，US2013/130378中所闡述之核苷及寡核苷酸，該等文獻之全部內容在此係以引用的方式併入本文中。此項技術中已知可用於經修飾之核苷中之許多其他雙環及三環糖及糖替代物環系統。In some embodiments, the sugar surrogate comprises a non-cyclic portion. In certain embodiments, the sugar surrogate is an unblocked nucleic acid ("UNA"). UNA is an unblocked non-cyclic nucleic acid in which any bonds of the sugar have been removed, thereby forming an unblocked "sugar" residue. In one example, UNA also encompasses monomers in which the bond between C1'-C4' (i.e., the covalent carbon-oxygen-carbon bond between the C1' carbon and the C4' carbon) has been removed. In another example, the C2'-C3' bond of the sugar (i.e., the covalent carbon-carbon bond between the C2' carbon and the C3' carbon) has been removed. Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication Nos. 2013/0096289; 2013/0011922; and 2011/0313020, each of which is hereby incorporated by reference in its entirety. In certain embodiments, the sugar surrogate comprises a peptide nucleic acid ("PNA"), a non-cyclic butyl nucleic acid (e.g., see Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides as described in Manoharan et al., US2013/130378, the entire contents of which are hereby incorporated by reference in its entirety. Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

在某些態樣中，本揭示案係關於包含至少一種寡核苷酸之化合物，其中此種寡核苷酸之核苷包含一或多種類型之經修飾之糖及/或未經修飾之糖，該等糖以確定之模式或「糖模體」沿著寡核苷酸或其區域排列。在某些情況下，此等糖模體包括(但不限於)本文所闡述之糖修飾模式中之任一者。In certain aspects, the present disclosure relates to compounds comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotides comprise one or more types of modified sugars and/or unmodified sugars arranged in a defined pattern or "sugar motif" along the oligonucleotide or a region thereof. In certain instances, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.

在某些實施例中，寡核苷酸包含間隔體(gapmer)糖模體。間隔體寡核苷酸包含具有兩個外部「翼」區及一個中央或內部「空位」區之區域，或由該區域組成。空位區及翼區形成核苷鄰接序列，其中每一翼之大部分核苷糖不同於空位之大部分核苷糖。在某些實施例中，翼區包含大部分經修飾之糖，且空位包含大部分未經修飾之糖。在某些實施例中，空位之核苷為去氧核苷。具有間隔體糖模體之化合物闡述於例如美國專利8,790,919中，該專利之全部內容在此係以引用的方式併入本文中。In certain embodiments, the oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two external "wing" regions and a central or internal "gap" region. The gap region and the wing region form a nucleoside-adjacent sequence, wherein the majority of the nucleoside sugars of each wing are different from the majority of the nucleoside sugars of the gap. In certain embodiments, the wing region comprises a majority of modified sugars, and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleoside of the gap is a deoxynucleoside. Compounds with gapmer sugar motifs are described, for example, in U.S. Patent 8,790,919, the entire contents of which are incorporated herein by reference.

在某些實施例中，雙股化合物之一種或兩種寡核苷酸包含三聯體糖模體。具有三聯體糖模體之寡核苷酸在三個連續核苷上包含三個相同之糖修飾。在某些實施例中，三聯體位於寡核苷酸之裂解位點處或附近。在某些實施例中，雙股化合物之寡核苷酸可含有一個以上之三聯體糖模體。在某些實施例中，三聯體糖模體之相同糖修飾為2’-F修飾。具有三聯體糖模體之化合物揭示於例如美國專利10,668,170中，該專利之全部內容係以引用的方式併入本文中。In certain embodiments, one or both oligonucleotides of the double-stranded compound comprise a triplet sugar motif. An oligonucleotide having a triplet sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is located at or near the cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotide of the double-stranded compound may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. Compounds having triplet sugar motifs are disclosed, for example, in U.S. Patent No. 10,668,170, the entire contents of which are incorporated herein by reference.

在某些實施例中，雙股化合物之一種或兩種寡核苷酸包含四聯體糖模體。具有四聯體糖模體之寡核苷酸在四個連續核苷上包含四個相同之糖修飾。在某些實施例中，四聯體位於裂解位點處或附近。在某些實施例中，雙股化合物之寡核苷酸可含有一個以上之四聯體糖模體。在某些實施例中，四聯體糖模體之相同糖修飾為2’-F修飾。對於具有長度為19-23個核苷酸之雙鏈體區域之雙股化合物，反義寡核苷酸之裂解位點通常位於距5’端10、11及12個位置附近。在某些實施例中，自有義寡核苷酸5’端之第一核苷計數，或自有義寡核苷酸5’端雙鏈體區域內之第一配對核苷酸開始計數，四聯體糖模體位於有義寡核苷酸之8位、9位、10位、11位；9位、10位、11位、12位；10位、11位、12位、13位；11位、12位、13位、14位；或12位、13位、14位、15位。在某些實施例中，自反義寡核苷酸5’端之第一核苷計數，或自反義寡核苷酸5’端雙鏈體區域內之第一配對核苷酸開始計數，四聯體糖模體位於反義寡核苷酸之8位、9位、10位、11位；9位、10位、11位、12位；10位、11位、12位、13位；11位、12位、13位、14位；或12位、13位、14位、15位。裂解位點可根據雙股化合物之雙鏈體區域長度而變化，且可相應地改變四聯體之位置。In certain embodiments, one or both oligonucleotides of the double-stranded compound comprise a quadruplex sugar motif. An oligonucleotide having a quadruplex sugar motif comprises four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is located at or near the cleavage site. In certain embodiments, the oligonucleotides of the double-stranded compound may contain more than one quadruplex sugar motif. In certain embodiments, the identical sugar modification of the quadruplex sugar motif is a 2'-F modification. For double-stranded compounds having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically located near 10, 11, and 12 positions from the 5' end. In certain embodiments, counting from the first nucleoside at the 5' end of the sense oligonucleotide, or starting from the first paired nucleotide in the duplex region at the 5' end of the sense oligonucleotide, the quadruplex sugar motif is located at position 8, 9, 10, 11; position 9, 10, 11, 12; position 10, 11, 12, 13; position 11, 12, 13, 14; or position 12, 13, 14, 15 of the sense oligonucleotide. In certain embodiments, counting from the first nucleotide at the 5' end of the antisense oligonucleotide, or counting from the first paired nucleotide in the duplex region at the 5' end of the antisense oligonucleotide, the quadruplex sugar motif is located at position 8, 9, 10, 11; position 9, 10, 11, 12; position 10, 11, 12, 13; position 11, 12, 13, 14; or position 12, 13, 14, 15 of the antisense oligonucleotide. The cleavage site can vary depending on the length of the duplex region of the double-stranded compound, and the position of the quadruplex can be changed accordingly.

在某些實施例中，寡核苷酸包含交替性糖模體。在某些實施例中，雙股化合物之一種或兩種寡核苷酸包含交替性糖模體。具有交替性糖模體之寡核苷酸包含至少兩種不同的糖修飾，其中包含第一糖修飾之一或多個連續核苷與包含第二糖修飾之一或多個連續核苷及包含第三糖修飾之一或多個連續核苷等等交替。舉例而言，若A、B及C各自代表核苷之一種修飾類型，則交替性模體可為「ABABABABABAB...」、「AABBAABBAABB...」、「AABAABAABAAB...」、「AAABAAABAAAB...」、「AAABBBAAABBB...」或「ABCABCABCABC...」等。在某些實施例中，交替性糖模體沿著寡核苷酸重複至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23個鄰接核鹼基。在某些實施例中，交替性糖模體包含兩種不同的糖修飾。在某些實施例中，交替性糖模體包含2’-OMe及2’-F糖修飾。In some embodiments, the oligonucleotide comprises an alternating sugar motif. In some embodiments, one or both oligonucleotides of the double-stranded compound comprise an alternating sugar motif. The oligonucleotide having an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternate with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, and so on. For example, if A, B, and C each represent a modification type of a nucleoside, the alternating motif may be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB...", "AAABAAABAAAB...", "AAABBBAAABBB...", or "ABCABCABCABC...", and the like. In some embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 adjacent nucleobases along the oligonucleotide. In some embodiments, the alternating sugar motif comprises two different sugar modifications. In some embodiments, the alternating sugar motif comprises 2'-OMe and 2'-F sugar modifications.

在某些實施例中，寡核苷酸之每一核苷獨立地經本文所提供之一或多種糖修飾修飾。在某些實施例中，雙股化合物之每一寡核苷酸獨立地具有一或多個本文所提供之糖模體。在某些實施例中，含有糖模體之寡核苷酸完全經修飾，此乃因除包含糖模體之核苷以外的每一核苷均包含糖修飾。核鹼基修飾及模體In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications provided herein. In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs provided herein. In certain embodiments, an oligonucleotide containing a sugar motif is fully modified in that each nucleoside except the nucleoside containing the sugar motif contains a sugar modification.Nucleobase Modifications and Motifs

在某些實施例中，本文所闡述之化合物包含經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸包含一或多個包含經修飾之核鹼基的核苷。在某些實施例中，經修飾之寡核苷酸包含一或多個不包含核鹼基之核苷，稱為無鹼基核苷。In certain embodiments, the compounds described herein comprise modified oligonucleotides. In certain embodiments, the modified oligonucleotides comprise one or more nucleosides comprising modified nucleobases. In certain embodiments, the modified oligonucleotides comprise one or more nucleosides that do not comprise nucleobases, referred to as abasic nucleosides.

在某些實施例中，經修飾之核鹼基係選自：5-取代之嘧啶、6-氮雜嘧啶、烷基或炔基取代之嘧啶、烷基取代之嘌呤以及N-2、N-6及O-6取代之嘌呤。在某些實施例中，經修飾之核鹼基係選自：2-胺基丙基腺嘌呤、5-羥甲基胞嘧啶、5-甲基胞嘧啶、黃嘌呤、次黃嘌呤、2-胺基腺嘌呤、6-N-甲基鳥嘌呤、6-N-甲基腺嘌呤、2-丙基腺嘌呤、2-硫尿嘧啶、2-硫胸腺嘧啶及2-硫胞嘧啶、5-丙炔基(C≡C-CH₃)尿嘧啶、5-丙炔基胞嘧啶、6-偶氮尿嘧啶、6-偶氮胞嘧啶、6-偶氮胸腺嘧啶、5-核糖基尿嘧啶(假尿嘧啶)、4-硫尿嘧啶、8-鹵基、8-胺基、8-硫醇、8-硫代烷基、8-羥基、8-氮雜及其他8-取代之嘌呤；5-鹵基、具體而言5-溴、5-三氟甲基、5-鹵基尿嘧啶及5-鹵基胞嘧啶；7-甲基鳥嘌呤、7-甲基腺嘌呤、2-F-腺嘌呤、2-胺基腺嘌呤、7-去氮鳥嘌呤、7-去氮腺嘌呤、3-去氮鳥嘌呤、3-去氮腺嘌呤、6-N-苯甲醯基腺嘌呤、2-N-異丁醯基鳥嘌呤、4-N-苯甲醯基胞嘧啶、4-N-苯甲醯基尿嘧啶、5-甲基4-N-苯甲醯基胞嘧啶、5-甲基4-N-苯甲醯基尿嘧啶、通用鹼基、疏水性鹼基、混雜鹼基、大小擴大之鹼基及氟化鹼基。其他經修飾之核鹼基包括三環嘧啶，諸如1,3-二氮雜吩噁嗪-2-酮、1,3-二氮雜吩噻嗪-2-酮及9-(2-胺基乙氧基)-1,3-二氮雜吩噁嗪-2-酮(G夾)。經修飾之核鹼基亦可包括嘌呤或嘧啶鹼基經其他雜環置換之彼等核鹼基，該等其他雜環例如7-去氮-腺嘌呤、7-去氮鳥苷、2-胺基吡啶及2-吡啶酮。In certain embodiments, the modified nucleobase is selected from: 5-substituted pyrimidine, 6-azapyrimidine, alkyl or alkynyl substituted pyrimidine, alkyl substituted purine, and N-2, N-6 and O-6 substituted purine. In certain embodiments, the modified nucleobase is selected from: 2-aminopropyladenine, 5-hydroxymethylcytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C-CH₃ )uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halogen, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxy, 8-aza and other 8-substituted purines; 5-halogen, specifically 5-bromo, 5-trifluoromethyl, 5-halogenuracil and 5-halogencytosine; 7-methylguanine, 7-methyladenine, 2 -F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, mixed bases, size-expanded bases, and fluorinated bases. Other modified nucleobases include tricyclic pyrimidines such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenathiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-H). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced by other heterocycles such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone.

其他核鹼基包括以下文獻中所揭示之彼等核鹼基：美國專利3,687,808；Modified Nucleosides in Biochemistry, Biotechnology and Medicine，Herdewijn, P.編輯，Wiley-VCH, 2008；The Concise Encyclopedia Of Polymer Science And Engineering，第858-859頁; Kroschwitz, J.L.編輯，John Wiley & Sons, 1990, 858-859；Englisch等人，Angewandte Chemie，國際版，1991, 30, 613；Sanghvi, Y.S.，第15章，dsRNA Research and Applications，第289-302頁；Antisense Research and Applications, Crooke, S.T.及Lebleu, B.編輯，CRC Press, 1993, 273-288；Antisense Drug Technology, Crooke S.T.編輯，CRC Press, 2008, 163-166及442-443 (第6章及第15章)，該等文獻各自在此係以引用的方式併入本文中。Other nucleobases include those disclosed in the following references: U.S. Patent 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed., Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pp. 858-859; Kroschwitz, J.L. ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y.S., Chapter 15, dsRNA Research and Applications, pp. 289-302; Antisense Research and Applications, Crooke, S.T. and Lebleu, B. ed., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke S.T., ed., CRC Press, 2008, 163-166 and 442-443 (Chapter 6 and Chapter 15), each of which is hereby incorporated by reference.

教示某些上述經修飾之核鹼基以及其他經修飾之核鹼基之製備的公開案包括(但不限於)美國申請公開案第2003/0158403號及第2003/0175906號；美國專利4,845,205；5,130,302；5,134,066；5,175,273；5,367,066；5,432,272；5,434,257；5,457,187；5,459,255；5,484,908；5,502,177；5,525,711；5,552,540；5,587,469；5,594,121；5,596,091；5,614,617；5,645,985；5,681,941；5,811,534；5,750,692；5,948,903；5,587,470；5,457,191；5,763,588；5,830,653；5,808,027；6,005,096；6,015,886；6,147,200；6,166,197；6,166,199；6,222,025；6,235,887；6,380,368；6,528,640；6,639,062；6,617,438；7,045,610；7,427,672；及7,495,088，該等案件各自之全部內容在此係以引用的方式併入本文中。Publications that teach the preparation of some of the above-described modified nucleobases and other modified nucleobases include, but are not limited to, U.S. Application Publication Nos. 2003/0158403 and 2003/0175906; U.S. Patent Nos. 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066 ;5,432,272;5,434,257;5,457,187;5,459,255;5,484,908;5,502,177;5,5 25,711; 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617; 5,645,98 5;5,681,941;5,811,534;5,750,692;5,948,903;5,587,470;5,457,191;5, 763,588; 5,830,653; 5,808,027; 6,005,096; 6,015,886; 6,147,200; 6,166,1 and 7,495,088, each of which is hereby incorporated by reference in its entirety.

在某些實施例中，本文所闡述之化合物包含寡核苷酸。在某些實施例中，寡核苷酸包含以確定之模式或模體沿著寡核苷酸或其區域排列的經修飾及/或未經修飾之核鹼基。在某些實施例中，每一核鹼基均經修飾。在某些實施例中，核鹼基均不經修飾。在某些實施例中，每一嘌呤或每一嘧啶均經修飾。在某些實施例中，每一腺嘌呤均經修飾。在某些實施例中，每一鳥嘌呤均經修飾。在某些實施例中，每一胸腺嘧啶均經修飾。在某些實施例中，每一尿嘧啶均經修飾。在某些實施例中，每一胞嘧啶均經修飾。在某些實施例中，經修飾之寡核苷酸中之一些或所有胞嘧啶核鹼基為5-甲基胞嘧啶。In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, the oligonucleotides comprise modified and/or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or a region thereof. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases is modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in the modified oligonucleotides are 5-methylcytosine.

在某些實施例中，經修飾之寡核苷酸包含經修飾之核鹼基之嵌段。在某些此類實施例中，嵌段位於寡核苷酸之3’端。在某些實施例中，嵌段位於寡核苷酸之3’端的3個核苷內。在某些實施例中，嵌段位於寡核苷酸之5’端。在某些實施例中，嵌段位於寡核苷酸之5’端的3個核苷內。核苷間鍵聯修飾及模體In certain embodiments, the modified oligonucleotide comprises a block of modified nucleobases. In certain such embodiments, the block is located at the 3' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 3' end of the oligonucleotide. In certain embodiments, the block is located at the 5' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 5' end of the oligonucleotide.Internucleoside Linkage Modifications and Motifs

3'至5'磷酸二酯鍵聯係RNA及DNA之天然核苷間鍵聯。在某些實施例中，本文所闡述之化合物具有一或多個經修飾(亦即非天然)之核苷間鍵聯。某些非天然核苷間鍵聯可賦予合意性質，諸如細胞攝取增強、對靶核酸之親和力增強且在核酸酶存在下穩定性增加。代表性經修飾之含磷核苷間鍵聯包括(但不限於)磷酸三酯、烷基膦酸酯(例如甲基膦酸酯)、胺基磷酸酯及硫代磷酸酯(「P=S」)及二硫代磷酸酯(「HS-P=S」)。代表性不含磷之核苷間連接基團包括(但不限於)亞甲基甲基亞胺基(-CH₂-N(CH₃)-O-CH₂)、硫代二酯、硫羰胺基甲酸酯(-O-C(=O)(NH)-S-)；矽氧烷(-O-SiH₂-O-)；及N,N'-二甲基肼(-CH₂-N((CH₃)-N((CH₃)-)。含磷及不含磷核苷間鍵聯之製備方法為熟習此項技術者所熟知。中性核苷間鍵聯包括(但不限於)磷酸三酯、甲基膦酸酯、MMI (3'-CH₂-N(CH₃)-O-5')、醯胺-3 (3'-CH₂-C(=O)-N(H)-5')、醯胺-4 (3'-CH₂-N(H)-C(=O)-5')、甲縮醛(3'-O-CH₂-O-5')、甲氧基丙基及硫基甲縮醛(3'-S-CH₂-O-5')。其他中性核苷間鍵聯包括非離子鍵聯，其包含矽氧烷(二烷基矽氧烷)、羧酸酯、羧醯胺、硫化物、磺酸酯及醯胺(例如，參見Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi及P.D. Cook編輯，ACS Symposium Series 580; 第3章及第4章，40-65)。其他中性核苷間鍵聯包括包含混合之N、O、S及CH₂組成部分的非離子鍵聯。The 3' to 5' phosphodiester bond links the natural internucleoside linkages of RNA and DNA. In certain embodiments, the compounds described herein have one or more modified (i.e., non-natural) internucleoside linkages. Certain non-natural internucleoside linkages can impart desirable properties, such as enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative modified phosphorus-containing internucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonate), phosphoramidates, and phosphorothioates ("P=S") and phosphorodithioates ("HS-P=S"). Representative non-phosphorus-containing internucleoside linking groups include, but are not limited to, methylenemethylimine (-CH2_- N(_CH3 )-O-_CH2 ), thiodiester, thiocarbamate (-OC(=O)(NH)-S-); siloxane (-O-_SiH2 -O-); and N,N'-dimethylhydrazine (_-CH2 -N((_CH3 )-N((_CH3 )-). Methods for preparing phosphorus-containing and non-phosphorus-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriester, methylphosphonate, MMI (3'-_CH2 -N(_CH3 )-O-5'), amide-3 (3'-_CH2 -C(=O)-N(H)-5'), amide-4 (3'-_CH2 -N(H)-C(=O)-5'), formaldehyde (3'-O-_CH2 -O-5'), methoxypropyl and thioformaldehyde (3'-S-_CH2 -O-5'). Other neutral internucleoside linkages include non-ionic linkages including siloxanes (dialkylsiloxanes), carboxylates, carboxamides, sulfides, sulfonates and amides (e.g., see Carbohydrate Modifications in Antisense Research; YS Sanghvi and PD Cook, eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Other neutral internucleoside linkages include non-ionic linkages including mixed N, O, S and_CH2 components.

在某些實施例中，本文所提供之化合物包含至少一個經修飾之核苷間鍵聯。經修飾之核苷間鍵聯可位於寡核苷酸之任何位置。對於雙股化合物，經修飾之核苷間鍵聯可位於雙股化合物之有義寡核苷酸內、反義寡核苷酸內或該兩種寡核苷酸內。In certain embodiments, the compounds provided herein comprise at least one modified internucleoside linkage. The modified internucleoside linkage can be located at any position of the oligonucleotide. For double-stranded compounds, the modified internucleoside linkage can be located in the sense oligonucleotide, the antisense oligonucleotide, or both oligonucleotides of the double-stranded compound.

在某些實施例中，核苷間鍵聯修飾可發生在寡核苷酸之每個核苷上。在某些實施例中，核苷間鍵聯修飾可沿著寡核苷酸以交替模式發生。在某些實施例中，基本上每一核苷間連接基團均為磷酸酯核苷間鍵聯(P=O)。在某些實施例中，經修飾之寡核苷酸之每一核苷間連接基團為硫代磷酸酯(P=S)。在某些實施例中，經修飾之寡核苷酸之每一核苷間連接基團獨立地選自硫代磷酸酯及磷酸酯核苷間鍵聯。在某些實施例中，雙股化合物之每一寡核苷酸上之核苷間鍵聯修飾模式係相同的。在某些實施例中，雙股化合物之每一寡核苷酸上之核苷間鍵聯修飾模式係不同的。在某些實施例中，雙股化合物包含6-8個經修飾之核苷間鍵聯。在某些實施例中，該6-8個經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或烷基膦酸酯核苷間鍵聯。在某些實施例中，有義寡核苷酸在5’端及3’端中之任一者處或在該兩個末端包含至少兩個經修飾之核苷間鍵聯。在某些此類實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或烷基膦酸酯核苷間鍵聯。在某些實施例中，反義寡核苷酸在5’端及3’端中之任一者處或在該兩個末端包含至少兩個經修飾之核苷間鍵聯。在某些此類實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或烷基膦酸酯核苷間鍵聯。In certain embodiments, the internucleoside linkage modification may occur on each nucleoside of the oligonucleotide. In certain embodiments, the internucleoside linkage modification may occur in an alternating pattern along the oligonucleotide. In certain embodiments, substantially each internucleoside linkage group is a phosphate internucleoside linkage (P=O). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is a thiophosphate (P=S). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is independently selected from thiophosphate and phosphate internucleoside linkages. In certain embodiments, the internucleoside linkage modification pattern on each oligonucleotide of the double-stranded compound is the same. In certain embodiments, the internucleoside linkage modification pattern on each oligonucleotide of the double-stranded compound is different. In certain embodiments, the double-stranded compound comprises 6-8 modified internucleoside linkages. In certain embodiments, the 6-8 modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleoside linkages at either the 5' end and the 3' end or at both ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either the 5' end and the 3' end or at both ends. In certain such embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or an alkylphosphonate internucleoside linkage.

在某些實施例中，雙股化合物包含懸突區。在某些實施例中，雙股化合物在懸突區中包含硫代磷酸酯或烷基膦酸酯核苷間鍵聯修飾。在某些實施例中，雙股化合物包含連接懸突核苷酸與靠近該懸突核苷酸之配對核苷酸之硫代磷酸酯或烷基膦酸酯核苷間鍵聯。舉例而言，在末端三個核苷之間可能存在至少兩個硫代磷酸酯核苷間鍵聯，其中該三個核苷中之兩個為懸突核苷，且第三個為靠近懸突核苷之配對核苷。該三個末端核苷可位於反義寡核苷酸之3’端、有義寡核苷酸之3’端、反義寡核苷酸之5’端或有義寡核苷酸之5’端。In certain embodiments, the double-stranded compound comprises an overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage connecting an overhang nucleotide and a paired nucleotide proximal to the overhang nucleotide. For example, there may be at least two phosphorothioate internucleoside linkages between the terminal three nucleosides, wherein two of the three nucleosides are overhang nucleosides and the third is a paired nucleoside proximal to the overhang nucleoside. The three terminal nucleosides may be located at the 3' end of the antisense oligonucleotide, the 3' end of the sense oligonucleotide, the 5' end of the antisense oligonucleotide, or the 5' end of the sense oligonucleotide.

在某些實施例中，經修飾之寡核苷酸包含一或多個具有手性中心之核苷間鍵聯。代表性手性核苷間鍵聯包括(但不限於)烷基膦酸酯及硫代磷酸酯。可將包含具有手性中心之核苷間鍵聯的經修飾之寡核苷酸製備成包含立體隨機核苷間鍵聯的經修飾之寡核苷酸群體，或製備成包含呈特定立體化學構形之硫代磷酸酯鍵聯的經修飾之寡核苷酸群體。在某些實施例中，經修飾之寡核苷酸群體包含硫代磷酸酯核苷間鍵聯，其中所有該等硫代磷酸酯核苷間鍵聯均為立體隨機的。此等經修飾之寡核苷酸可使用可隨機選擇每一硫代磷酸酯鍵聯之立體化學構形之合成方法來生成。如熟習此項技術者所充分理解，每一個別寡核苷酸分子之每一個別硫代磷酸酯具有確定之立體構形。在某些實施例中，經修飾之寡核苷酸群體富集經修飾之寡核苷酸，該等經修飾之寡核苷酸包含一或多個呈特定獨立選擇之立體化學構形之特定硫代磷酸酯核苷間鍵聯。在某些實施例中，群體中至少65%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少70%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少80%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少90%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少99%之分子中存在特定硫代磷酸酯鍵聯之特定構形。經修飾之寡核苷酸之此類富集群體可使用此項技術中已知之合成方法來生成，例如以下文獻中所闡述之方法：Oka等人，JACS 125, 8307 (2003)；Wan等人，Nuc. Acid. Res. 42, 13456 (2014)；及WO 2017/015555。在某些實施例中，經修飾之寡核苷酸群體富集具有至少一種呈(Sp)構形之所指示硫代磷酸酯的經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸群體富集具有至少一種呈(Rp)構形之硫代磷酸酯的經修飾之寡核苷酸。結合基團In certain embodiments, the modified oligonucleotide comprises one or more internucleoside linkages having a chiral center. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as a modified oligonucleotide population comprising stereo-random internucleoside linkages, or as a modified oligonucleotide population comprising phosphorothioate linkages in a specific stereochemical configuration. In certain embodiments, the modified oligonucleotide population comprises phosphorothioate internucleoside linkages, wherein all of the phosphorothioate internucleoside linkages are stereo-random. Such modified oligonucleotides can be generated using a synthetic method that can randomly select the stereochemical configuration of each phosphorothioate linkage. As is well understood by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereo configuration. In certain embodiments, a modified oligonucleotide population is enriched for modified oligonucleotides that contain one or more specific phosphorothioate internucleoside linkages in a specific independently selected stereochemical configuration. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, a specific conformation of a specific phosphorothioate linkage is present in at least 99% of the molecules in the population. Such enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, such as those described in Oka et al., JACS 125, 8307 (2003); Wan et al., Nuc. Acid. Res. 42, 13456 (2014); and WO 2017/015555. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in a (Sp) conformation. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in a (Rp) conformation.Binding Group

在某些實施例中，本文所闡述之化合物包含一或多種寡核苷酸及視情況一或多種結合基團，或由其組成。結合基團可連接至寡核苷酸之任一端或兩端及/或連接在任一內部位置。在某些實施例中，結合基團連接在寡核苷酸之3’端。在某些實施例中，結合基團連接在寡核苷酸之5’端。在某些實施例中，寡核苷酸共價連接至一或多種結合基團。In certain embodiments, the compounds described herein comprise or consist of one or more oligonucleotides and optionally one or more binding groups. The binding group may be attached to either or both ends of the oligonucleotide and/or to any internal position. In certain embodiments, the binding group is attached to the 3' end of the oligonucleotide. In certain embodiments, the binding group is attached to the 5' end of the oligonucleotide. In certain embodiments, the oligonucleotide is covalently attached to one or more binding groups.

在某些實施例中，結合基團為連接至寡核苷酸之任一端或兩端之末端基團。在某些此類實施例中，末端基團連接在寡核苷酸之3’端。在某些此類實施例中，末端基團連接在寡核苷酸之5’端。在某些實施例中，末端基團包括(但不限於)封端基團、磷酸酯部分、保護基團、經修飾或未經修飾之核苷及兩個或更多個獨立地經修飾或未經修飾之核苷，諸如懸突。In some embodiments, the binding group is a terminal group attached to either or both ends of the oligonucleotide. In some such embodiments, the terminal group is attached to the 3' end of the oligonucleotide. In some such embodiments, the terminal group is attached to the 5' end of the oligonucleotide. In some embodiments, the terminal group includes (but is not limited to) a capping group, a phosphate moiety, a protecting group, a modified or unmodified nucleoside, and two or more independently modified or unmodified nucleosides, such as an overhang.

在某些實施例中，結合基團使所連接之寡核苷酸之一或多種性質改質，包括(但不限於)藥效學、藥物動力學、穩定性、活性、半衰期、結合、吸收、組織分佈、細胞分佈、細胞攝取、電荷及清除。在某些實施例中，例如與不存在結合基團之化合物相比，此一結合基團增強化合物對選定靶標(例如分子、細胞或細胞類型、區室(例如細胞或器官區室)、組織、器官或身體區域)之親和力。在某些實施例中，結合基團賦予所連接之寡核苷酸新的性質，例如使得能夠偵測寡核苷酸之螢光團或報導基團。In some embodiments, the binding group modifies one or more properties of the linked oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, activity, half-life, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge, and clearance. In some embodiments, such a binding group enhances the affinity of the compound for a selected target (e.g., a molecule, a cell or cell type, a compartment (e.g., a cell or organ compartment), a tissue, an organ, or a body region), for example, compared to the compound in the absence of the binding group. In some embodiments, the binding group imparts a new property to the linked oligonucleotide, such as a fluorophore or reporter group that enables detection of the oligonucleotide.

在某些實施例中，結合基團包括(但不限於)嵌插物、報導分子、聚胺、聚醯胺、肽、碳水化合物、維生素部分、聚乙二醇、硫醚、聚醚、膽固醇、硫膽固醇、膽酸部分、葉酸鹽、脂質、磷脂、生物素、吩嗪、菲啶、蒽醌、金剛烷、吖啶、螢光黃、玫瑰紅、香豆素、螢光團及染料。In certain embodiments, binding groups include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterol, sulfosterol, bile acid moieties, folates, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluorescent yellow, rose bengal, coumarin, fluorescein, and dyes.

在某些實施例中，結合基團包括活性原料藥，例如阿司匹林(aspirin)、華法林(warfarin)、苯丁吡唑酮(phenylbutazone)、布洛芬、舒洛芬(suprofen)、芬布芬(fen-bufen)、酮洛芬(ketoprofen)、(S)-(+)-普拉洛芬(pranoprofen)、卡洛芬(carprofen)、丹磺醯肌胺酸(dansylsarcosine)、2,3,5-三碘苯甲酸、芬戈莫德(fingolimod)、氟芬那酸(flufenamic acid)、醛葉酸、苯并噻二嗪、氯噻嗪、二氮呯、吲哚美辛(indo-methicin)、巴比妥酸鹽(barbiturate)、頭孢菌素(cephalosporin)、磺胺藥、抗糖尿病藥、抗細菌劑或抗生素。In certain embodiments, the conjugated group comprises an active pharmaceutical ingredient, such as aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folate, benzothiadiazine, chlorothiazide, diazepam, indomethicin, barbiturate, cephalosporin, sulfonamide, antidiabetic, antibacterial, or antibiotic.

在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包括(但不限於)凝集素、糖蛋白、脂質、蛋白質、肽、肽模擬物、受體配位體、抗體、促甲狀腺素、黑促素、表面活性劑蛋白A、碳水化合物、碳水化合物衍生物、經修飾之碳水化合物、碳水化合物群集、多糖、經修飾之多糖或多糖衍生物、黏蛋白碳水化合物、多價乳糖、多價半乳糖、N-乙醯基-半乳胺糖(GalNAc)、N-乙醯基葡萄糖胺多價甘露糖、多價岩藻糖、糖基化聚胺基酸、多價半乳糖、運鐵蛋白、雙膦酸酯、聚麩胺酸鹽、聚天冬胺酸鹽、脂質、膽固醇、類固醇、膽汁酸、葉酸鹽、維生素B12、維生素A、生物素或RGD肽或RGD肽模擬物。In certain embodiments, the binding group is a targeting moiety. In certain embodiments, targeting moieties include, but are not limited to, lectins, glycoproteins, lipids, proteins, peptides, peptide mimetics, receptor ligands, antibodies, thyrotropin, melanogaster, surfactant protein A, carbohydrates, carbohydrate derivatives, modified carbohydrates, carbohydrate clusters, polysaccharides, modified polysaccharides or polysaccharide derivatives, mucin carbohydrates, multivalent lactose, multivalent galactose, N-acetyl-galactosamine sugar (GalNAc), N-acetylglucosamine multivalent mannose, multivalent fucose, glycosylated polyamino acids, multivalent galactose, transferrin, bisphosphonates, polyglutamine, polyaspartate, lipids, cholesterol, steroids, bile acid, folate, vitamin B12, vitamin A, biotin, or RGD peptide or RGD peptide mimetic.

在某些實施例中，結合基團可包括(但不限於)以下參考文獻中所闡述之結合基團，諸如膽固醇(例如Letsinger等人，Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556)；膽酸(例如Manoharan等人，Biorg. Med. Chem. Let., 1994, 4:1053-1060)；硫醚，例如己基-S-三苯甲基硫醇(例如Manoharan等人，Αnn. NY. Acad. Sci., 1992, 660:306-309；Manoharan等人，Biorg. Med. Chem. Let., 1993, 3:2765-2770)；硫膽固醇(例如Oberhauser等人，Nucl. Acids Res., 1992, 20:533-538)；脂肪族鏈，例如十二烷-二醇或十一烷基殘餘物(例如Saison-Behmoaras等人，EMBO J, 1991, 10:1111-1118；Kabanov等人，FEBS Lett., 1990, 259:327-330；Svinarchuk等人，Biochimie, 1993, 75:49-54)；磷脂，例如二-十六烷基-外消旋-甘油或1,2-二-O-十六烷基-外消旋-甘油-3-H-膦酸三乙基-銨(例如Manoharan等人，Tetrahedron Lett., 1995, 36:3651-3654；Shea等人，Nucl. Acids Res., 1990, 18:3777-3783)；聚胺或聚乙二醇鏈(例如Manoharan等人，Nucleosides & Nucleotides, 1995, 14:969-973)；金剛烷乙酸(例如Manoharan等人，Tetrahedron Lett., 1995, 36:3651-3654)；棕櫚基(例如Mishra等人，Biochim. Biophys. Acta, 1995, 1264:229-237)；十八烷基胺或己基胺基-羰基羥膽固醇部分(例如Crooke等人，J. Pharmacol. Exp. Ther., 1996, 277:923-937)；生育酚(例如Nishina等人，Molecular Therapy Nucleic Acids, 2015, 4, e220及Nishina等人，Molecular Therapy, 2008, 16:734-740)；GalNAc及其他碳水化合物(例如Maier等人，Bioconjugate Chemistry, 2003, 14, 18-29；Rensen等人，J. Med. Chem. 2004, 47, 5798-5808；WO2009/073809及美國專利8,106,022；8,450,467及8,828,957；及WO2014/179445；WO2014/179620及美國專利9,127,276；9,181,549及10,844,379)，該等文獻各自係以全文引用的方式併入本文中。In certain embodiments, the binding group may include, but is not limited to, the binding groups described in the following references, such as cholesterol (e.g., Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556); cholic acid (e.g., Manoharan et al., Biorg. Med. Chem. Let., 1994, 4: 1053-1060); thioethers, such as hexyl-S-tritylthiol (e.g., Manoharan et al., Annals of New York, 1992, 660: 306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3: 2765-2770); thiocholesterol (e.g., Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538); aliphatic chains, such as dodecanediol or undecyl residues (e.g. Saison-Behmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54); phospholipids, such as di-hexadecyl-rac-glycerol or 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonic acid triethyl-ammonium (e.g. Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783); polyamine or polyethylene glycol chain (e.g., Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973); adamantane acetic acid (e.g., Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654); palmityl (e.g., Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237); octadecylamine or hexylamino-carbonyl hydroxycholesterol moiety (e.g., Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923-937); tocopherol (e.g., Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220 and Nishina et al., Molecular Therapy, 2008, 16:734-740); GalNAc and other carbohydrates (e.g., Maier et al., Bioconjugate Chemistry, 2003, 14, 18-29; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; WO2009/073809 and U.S. Pat. Nos. 8,106,022; 8,450,467 and 8,828,957; and WO2014/179445; WO2014/179620 and U.S. Pat. Nos. 9,127,276; 9,181,549 and 10,844,379), each of which is incorporated herein by reference in its entirety.

結合基團可經由結合連接體連接至寡核苷酸。在某些實施例中，結合連接體包含鏈結構，諸如烴基鏈，或重複單元之寡聚物或此等重複單元之組合。在某些實施例中，結合連接體包含一或多個選自以下之基團：烷基、胺基、側氧基、醯胺、二硫化物、聚乙二醇、醚、硫醚及羥基胺基。在某些實施例中，結合連接體包含至少一個磷基。在某些實施例中，結合連接體包含至少一個磷酸酯基。在某些實施例中，結合連接體包括至少一個中性連接基團。在某些實施例中，結合連接體包括(但不限於)吡咯啶、8-胺基-3,6-二氧雜辛酸(ADO)、4-(N-馬來醯亞胺基甲基)環己烷-1-甲酸琥珀醯亞胺酯(SMCC)及6-胺基己酸(AHEX或AHA)。其他結合連接體包括(但不限於)經取代或未經取代之C₁-C₁₀烷基、經取代或未經取代之C₂-C₁₀烯基或經取代或未經取代之C₂-C₁₀炔基，其中較佳取代基之非限制性清單包括羥基、胺基、烷氧基、羧基、苯甲基、苯基、硝基、硫醇、硫烷氧基、鹵素、烷基、芳基、烯基及炔基。在某些實施例中，結合連接體包含1-10個連接體核苷。在某些實施例中，此等連接體核苷可為經修飾或未經修飾之核苷。通常期望連接體核苷在化合物到達靶組織後自化合物裂解。因此，本文之連接體核苷可經由可裂解鍵彼此連接及連接至化合物之其餘部分。在本文中，連接體核苷不視為寡核苷酸之一部分。因此，在化合物包含由指定數目或範圍之連接核苷組成及/或與參照核酸具有指定互補性百分比之寡核苷酸且化合物亦包含含有結合連接體(包含連接體核苷)之結合基團的實施例中，彼等連接體核苷不計入寡核苷酸之長度且不用於確定寡核苷酸對於參照核酸之互補性百分比。The binding group can be linked to the oligonucleotide via a binding linker. In some embodiments, the binding linker comprises a chain structure, such as an alkyl chain, or an oligomer of repeating units or a combination of such repeating units. In some embodiments, the binding linker comprises one or more groups selected from the following: alkyl, amine, pendoxy, amide, disulfide, polyethylene glycol, ether, thioether and hydroxylamine. In some embodiments, the binding linker comprises at least one phosphorus group. In some embodiments, the binding linker comprises at least one phosphate group. In some embodiments, the binding linker includes at least one neutral linking group. In certain embodiments, the conjugate linker includes, but is not limited to, pyrrolidine, 8-amino-3,6-dioxooctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include, but are not limited to, substituted or unsubstituted C₁ -C₁₀ alkyl, substituted or unsubstituted C₂ -C₁₀ alkenyl, or substituted or unsubstituted C₂ -C₁₀ alkynyl, wherein a non-limiting list of preferred substituents includes hydroxyl, amino, alkoxy, carboxyl, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the conjugate linker comprises 1-10 linker nucleosides. In certain embodiments, these linker nucleosides may be modified or unmodified nucleosides. It is generally expected that the linker nucleosides will cleave from the compound after the compound reaches the target tissue. Therefore, the linker nucleosides herein may be linked to each other and to the rest of the compound via a cleavable bond. In this article, the linker nucleosides are not considered part of the oligonucleotide. Therefore, in embodiments in which the compound comprises an oligonucleotide composed of a specified number or range of linker nucleosides and/or has a specified percentage of complementarity with a reference nucleic acid and the compound also comprises a binding group containing a binding linker (including a linker nucleoside), those linker nucleosides are not included in the length of the oligonucleotide and are not used to determine the percentage of complementarity of the oligonucleotide to the reference nucleic acid.

在某些實施例中，結合基團及結合連接體以及其他修飾包括(但不限於)以下參考文獻中所闡述者：US 5,994,517；US 6,300,319；US 6,660,720；US 6,906,182；US 7,262,177；US 7,491,805；US 8,106,022；US 7,723,509；US 9,127,276；US 2006/0148740；US 2011/0123520；WO2013/033230；WO2012/037254；Biessen等人，J. Med. Chem. 1995, 38, 1846-1852；Lee等人，Bioorganic & Medicinal Chemistry 2011,19, 2494-2500；Rensen等人，J. Biol. Chem. 2001, 276, 37577-37584；Rensen等人，J. Med. Chem. 2004, 47, 5798-5808；Sliedregt等人，J. Med. Chem. 1999, 42, 609-618；Valentijn等人，Tetrahedron, 1997, 53, 759-770；Lee, Carhohydr Res, 1978, 67, 509-514；Connolly等人，J Biol Chem, 1982, 257, 939-945；Pavia等人，Int J Pep Protein Res, 1983, 22, 539-548；Lee等人，Biochem, 1984, 23, 4255-4261；Lee等人，Glycoconjugate J, 1987, 4, 317-328；Toyokuni等人，Tetrahedron Lett, 1990, 31, 2673-2676；Biessen等人，J Med Chem, 1995, 38, 1538-1546；Valentijn等人，Tetrahedron, 1997, 53, 759-770；Kim等人，Tetrahedron Lett, 1997, 38, 3487-3490；Lee等人，Bioconjug Chem, 1997, 8, 762-765；Kato等人，Glycohiol, 2001, 11, 821-829；Rensen等人，J Biol Chem, 2001, 276, 37577-37584；Lee等人，Methods Enzymol, 2003, 362, 38-43；Westerlind等人，Glycoconj J, 2004, 21, 227-241；Lee等人，Bioorg Med Chem Lett, 2006, 16(19), 5132-5135；Maierhofer等人，Bioorg Med Chem, 2007, 15, 7661-7676；Khorev等人，Bioorg Med Chem, 2008, 16, 5216-5231；Lee等人，Bioorg Med Chem, 2011, 19, 2494-2500；Kornilova等人，Analyt Biochem, 2012, 425, 43-46；Pujol等人，Angew Chemie Int Ed Engl, 2012, 51, 7445-7448；Biessen等人，J Med Chem, 1995, 38, 1846-1852；Sliedregt等人，J Med Chem, 1999, 42, 609-618；Rensen等人，J Med Chem, 2004, 47, 5798-5808；Rensen等人，Arterioscler Thromh Vase Biol, 2006, 26, 169-175；van Rossenberg等人，Gene Ther, 2004, 11, 457-464；Sato等人，JAm Chem Soc, 2004, 126, 14013-14022；Lee等人，J Org Chem, 2012, 77, 7564-7571；Biessen等人，FASEB J, 2000, 14, 1784-1792；Rajur等人，Bioconjug Chem, 1997, 8, 935-940；Duff等人，Methods Enzymol, 2000, 313, 297-321；Maier等人，Bioconjug Chem, 2003, 14, 18-29；Jayaprakash等人，Org Lett, 2010, 12, 5410-5413；Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128；Merwin等人，Bioconjug Chem, 1994, 5, 612-620；Tomiya等人，Bioorg Med Chem, 2013, 21, 5275-5281；國際申請案WO1998/013381；WO2011/038356；WO1997/046098；W02008/098788；W02004/101619；WO2012/037254；WO2011/120053；WO2011/100131；WO2011/163121；WO2012/177947；W02013/033230；W02013/075035；WO2012/083185；WO2012/083046；W02009/082607；WO2009/134487；W02010/144740；W02010/148013；WO1997/020563；W02010/088537；W02002/043771；W02010/129709；WO2012/068187；WO2009/126933；W02004/024757；WO2010/054406；WO2012/089352；WO2012/089602；WO2013/166121；WO2013/165816；美國專利4,751,219；7,582,744；8,552,163；8,137,695；6,908,903；6,383,812；7,262,177；6,525,031；5,994,517；6,660,720；6,300,319；7,723,509；8,106,022；7,491,805；7,491,805；8,541,548；8,344,125；8,313,772；8,349,308；8,450,467；8,501,930；8,158,601；7,262,177；6,906,182；6,620,916；8,435,491；8,404,862；7,851,615；已公佈之美國專利申請公開案US2011/0097264；US2011/0097265；US2013/0004427；US2003/0119724；US2011/0207799；US2012/0035115；US2012/0230938；US2005/0164235；US2006/0183886；US2012/0136042；US2012/0095075；US2013/0109817；US2006/0148740；US2008/0206869；US2012/0165393；US2012/0101148；US2013/0121954；US2011/0123520；US2003/0077829；US2008/0108801；及US2009/0203132；該等參考文獻各自係以全文引用的方式併入本文中。某些結合基團In certain embodiments, the binding groups and binding linkers and other modifications include, but are not limited to, those described in the following references: US 5,994,517; US 6,300,319; US 6,660,720; US 6,906,182; US 7,262,177; US 7,491,805; US 8,106,022; US 7,723,509; US 9,127,276; US 2006/0148740; US 2011/0123520; WO2013/033230; WO2012/037254; Biessen et al., J. Med. Chem. 1995, 38, 1846-1852; Lee et al., Bioorganic & Medicinal Chemistry 2011, 19, 2494-2500; Rensen et al., J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al., J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al., J. Med. Chem. 1999, 42, 609-618; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Lee, Carhohydr Res, 1978, 67, 509-514; Connolly et al., J Biol Chem, 1982, 257, 939-945; Pavia et al., Int J Pep Protein Res, 1983, 22, 539-548; Lee et al., Biochem, 1984, 23, 4255-4261; Lee et al., Glycoconjugate J, 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett, 1990, 31, 2673-2676; Biessen et al., J Med Chem, 1995, 38, 1538-1546; Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al., Tetrahedron Lett, 1997, 38, 3487-3490; Lee et al., Bioconjug Chem, 1997, 8, 762-765; Kato et al., Glycohiol, 2001, 11, 821-829; Rensen et al., J Biol Chem, 2001, 276, 37577-37584; Lee et al., Methods Enzymol, 2003, 362, 38-43; Westerlind et al., Glycoconj J, 2004, 21, 227-241; Lee et al., Bioorg Med Chem Lett, 2006, 16(19), 5132-5135; Maierhofer et al., Bioorg Med Chem, 2007, 15, 7661-7676; Khorev et al., Bioorg Med Chem, 2008, 16, 5216-5231; Lee et al., Bioorg Med Chem, 2011, 19, 2494-2500; Kornilova et al., Analyt Biochem, 2012, 425, 43-46; Pujol et al., Angew Chemie Int Ed Engl, 2012, 51, 7445-7448; Biessen et al., J Med Chem, 1995, 38, 1846-1852; Sliedregt et al., J Med Chem, 1999, 42, 609-618; Rensen et al., J Med Chem, 2004, 47, 5798-5808; Rensen et al., Arterioscler Thromh Vase Biol, 2006, 26, 169-175; van Rossenberg et al., Gene Ther, 2004, 11, 457-464; Sato et al., J Am Chem Soc, 2004, 126, 14013-14022; Lee et al., J Org Chem, 2012, 77, 7564-7571; Biessen et al., FASEB J, 2000, 14, 1784-1792; Rajur et al., Bioconjug Chem, 1997, 8, 935-940; Duff et al., Methods Enzymol, 2000, 313, 297-321; Maier et al., Bioconjug Chem, 2003, 14, 18-29; Jayaprakash et al., Org Lett, 2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128; Merwin et al., Bioconjug Chem, 1994, 5, 612-620; Tomiya et al., Bioorg Med Chem, 2013, 21, 5275-5281; International applications WO1998/013381; WO2011/038356; WO1997/046098; WO2008/098788; WO2004/101619; WO2012/037254; WO2011/120053; WO2011/100131; WO2011 /163121;WO2012/177947;W02013/033230;W02013/075035;WO2012/083185;WO2 012/083046; W02009/082607; WO2009/134487; W02010/144740; W02010/148013; WO1997/020563; W02010/088537; W02002/043771; W02010/129709; WO2012/0681 87; WO2009/126933; W02004/024757; WO2010/054406; WO2012/089352; WO2012/0 89602; WO2013/166121; WO2013/165816; U.S. Patents 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660, 720; 6,300,319; 7,723,509; 8,106,022; 7,491,805; 7,491,805; 8,541,548; 8,3 44,125; 8,313,772; 8,349,308; 8,450,467; 8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491; 8,404,862; 7,851,615; published U.S. patent applications US2011/0097264; US2011/0097265; US2013/0004427; US2003/0119724; US2011/0207 799; US2012/0035115; US2012/0230938; US2005/0164235; US2006/0183886; US2 012/0136042; US2012/0095075; US2013/0109817; US2006/0148740; US2008/020 6869; US2012/0165393; US2012/0101148; US2013/0121954; US2011/0123520; US2003/0077829; US2008/0108801; and US2009/0203132; each of which is incorporated herein by reference in its entirety.Certain Binding Groups

在某些實施例中，本文所提供之化合物包含結合基團。在某些實施例中，本文所提供之寡核苷酸包含結合基團。在某些實施例中，結合基團為靶向部分。在某些實施例中，靶向部分包含一或多種TrkB配位體。In certain embodiments, the compounds provided herein include a binding group. In certain embodiments, the oligonucleotides provided herein include a binding group. In certain embodiments, the binding group is a targeting moiety. In certain embodiments, the targeting moiety includes one or more TrkB ligands.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體具有式(I)或為其鹽、溶劑合物或水合物：式(I)， 其中： R¹為經修飾之寡核苷酸； L¹、L²、L³及L⁴係如本文所闡述； R²為氫、-OR⁷、-SR⁸或-NR⁹R¹⁰； R³為氫、-OR¹¹、-SR¹²或-NR¹³R¹⁴； R⁴為氫、-OR¹⁵、-SR¹⁶或-NR¹⁷R¹⁸； R⁵為氫、-OR¹⁹、-SR²⁰或-NR²¹R²²； R⁶為氫、-OH、視情況經取代之-O-烷基、視情況經取代之-OAc、-NH₂、視情況經取代之-NHAc、-SH或=O； R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹及R²²各自獨立地為氫、視情況經取代之烷基、視情況經取代之雜烷基、視情況經取代之環烷基、視情況經取代之雜環烷基、視情況經取代之芳基、視情況經取代之雜芳基； Y為CH₂、NH、S或O；且 Z為視情況經取代之芳基或視情況經取代之雜芳基。In certain embodiments, the TrkB ligand of the modified oligonucleotide has formula (I) or is a salt, solvate or hydrate thereof: Formula (I), wherein: R¹ is a modified oligonucleotide; L¹ , L² , L³ and L⁴ are as described herein; R² is hydrogen, -OR⁷ , -SR⁸ or -NR⁹ R¹⁰ ; R³ is hydrogen, -OR¹¹ , -SR¹² or -NR¹³ R¹⁴ ; R⁴ is hydrogen, -OR¹⁵ , -SR¹⁶ or -NR¹⁷ R¹⁸ ; R⁵ is hydrogen, -OR¹⁹ , -SR²⁰ or -NR²¹ R²² ; R⁶ is hydrogen, -OH, optionally substituted -O-alkyl, optionally substituted -OAc, -NH₂ , optionally substituted -NHAc, -SH or =O; R⁷ , R⁸ , R⁹ , R^R10 ,^R11 ,^R12 ,^R13 ,^R14 ,^R15 ,^R16 ,^R17 ,^R18 ,^R19 ,^R20 ,^R21 and^R22 are each independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; Y is_CH2 , NH, S or O; and Z is optionally substituted aryl or optionally substituted heteroaryl.

在某些實施例中，R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁸、R¹⁹、R²⁰、R²¹及R²²各自獨立地為視情況經取代之不飽和或部分不飽和烷基。在某些實施例中，R⁷、R⁸、R⁹及R¹⁰各自獨立地為烯基。在某些實施例中，R⁷、R⁸、R⁹及R¹⁰各自獨立地為炔基。In certain embodiments, R⁷ , R⁸ , R⁹ , R¹⁰ , R¹¹ , R¹² , R¹³ , R¹⁴ , R¹⁵ , R¹⁶ , R¹⁷ , R¹⁸ , R¹⁹ , R²⁰ , R²¹ and R²² are each independently an optionally substituted unsaturated or partially unsaturated alkyl group. In certain embodiments, R⁷ , R⁸ , R⁹ and R¹⁰ are each independently an alkenyl group. In certain embodiments, R⁷ , R⁸ , R⁹ and R¹⁰ are each independently an alkynyl group.

在某些實施例中，R²為OR⁷。在某些實施例中，R³為OR¹¹。在某些實施例中，R⁷及R¹¹各自獨立地為氫、視情況經取代之烷基或視情況經取代之烯基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為氫。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為視情況經取代之烷基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為視情況經取代之不飽和或部分不飽和烷基。在某些實施例中，R⁷及R¹¹中之一者或兩者各自獨立地為烯基。在某些實施例中，R⁷為視情況經取代之烷基且R¹¹為氫。在某些實施例中，R⁷為氫且R¹¹為視情況經取代之烷基。在某些實施例中，R⁷為烯基且R¹¹為氫。在某些實施例中，R⁷為氫且R¹¹為視情況經取代之烯基。In certain embodiments, R² is OR⁷ . In certain embodiments, R³ is OR¹¹ . In certain embodiments, R⁷ and R¹¹ are each independently hydrogen, optionally substituted alkyl, or optionally substituted alkenyl. In certain embodiments, one or both of R⁷ and R¹¹ are each independently hydrogen. In certain embodiments, one or both of R⁷ and R¹¹ are each independently hydrogen. In certain embodiments, one or both of R⁷ and R¹¹ are each independently substituted alkyl. In certain embodiments, one or both of R 7 and R 11 are each independently unsaturated or partially unsaturated alkyl, which may be substituted. In certain embodiments, one or both of R⁷ and R¹¹ are each independently alkenyl. In certain embodiments, R⁷ is optionally substituted alkyl and R¹¹ is hydrogen. In certain embodiments, R⁷ is hydrogen and R¹¹ is optionally substituted alkyl. In certain embodiments, R⁷ is alkenyl and R¹¹ is hydrogen. In certain embodiments, R⁷ is hydrogen and R¹¹ is optionally substituted alkenyl.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體係選自以下各式或其鹽、溶劑合物或水合物：式(II-A)、式(II-B)、式(II-C)， 其中： R¹為經修飾之寡核苷酸；且 L¹、L²、L³及L⁴係如本文所闡述。In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (II-A), Formula (II-B), Formula (II-C), wherein: R¹ is a modified oligonucleotide; and L¹ , L² , L³ and L⁴ are as described herein.

在某些實施例中，L¹、L²、L³及L⁴各自獨立地不存在，為鍵、視情況經取代之烷基連接體、視情況經取代之聚乙二醇(PEG)連接體、視情況經取代之雜烷基連接體或視情況經取代之雜芳基連接體。In certain embodiments, L¹ , L² , L³ and L⁴ are each independently absent, a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker or an optionally substituted heteroaryl linker.

在某些實施例中，L¹為視情況經取代之雜芳基連接體。In certain embodiments, L¹ is an optionally substituted heteroaryl linker.

在某些實施例中，L¹為視情況經取代之不飽和雜芳基、視情況經取代之雜芳基或視情況經取代之飽和或部分不飽和雜環烷基連接體。In certain embodiments, L¹ is an optionally substituted unsaturated heteroaryl, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

在某些實施例中，L¹包含結構：。In certain embodiments,^L1 comprises the structure: .

在某些實施例中，L¹為視情況經取代之雜烷基連接體。在某些實施例中，視情況經取代之雜烷基連接體為視情況經取代之雜烷基或視情況經取代之C₁-C₁₀烷基鏈，其中一或多個碳原子經O、N或S置換。In certain embodiments, L¹ is an optionally substituted heteroalkyl linker. In certain embodiments, the optionally substituted heteroalkyl linker is an optionally substituted heteroalkyl or an optionally substituted C₁ -C₁₀ alkyl chain in which one or more carbon atoms are replaced by O, N or S.

在某些實施例中，L¹包含結構：或。In certain embodiments,^L1 comprises the structure: or .

在某些實施例中，L¹包含結構：或-N(CH3)-。In certain embodiments,^L1 comprises the structure: Or -N(CH3)-.

在某些實施例中，L²為視情況經取代之PEG連接體。In certain embodiments,^L2 is an optionally substituted PEG linker.

在某些實施例中，PEG連接體之長度為五個PEG單元。在某些實施例中，PEG連接體之長度為四個PEG單元。在某些實施例中，PEG連接體之長度為三個PEG單元。In some embodiments, the PEG conjugate is five PEG units in length. In some embodiments, the PEG conjugate is four PEG units in length. In some embodiments, the PEG conjugate is three PEG units in length.

在某些實施例中，L²為視情況經取代之烷基連接體。在某些實施例中，L²為視情況經取代之C₁-₂₀烷基連接體。在某些實施例中，L²為視情況經取代之C₈烷基連接體。在某些實施例中，L³為視情況經取代之雜芳基連接體。In some embodiments,^L2 is an optionally substituted alkyl linker. In some embodiments,^L2 is an optionally substituted_C1-20 alkyl linker. In some embodiments,^L2 is an optionally substituted_C8alkyl linker. In some embodiments,^L3 is an optionally substituted heteroaryl linker.

在某些實施例中，L³為視情況經取代之部分不飽和雜芳基連接體、視情況經取代之雜芳基或視情況經取代之飽和或部分不飽和雜環烷基連接體。In certain embodiments, L³ is an optionally substituted partially unsaturated heteroaryl linker, an optionally substituted heteroaryl, or an optionally substituted saturated or partially unsaturated heterocycloalkyl linker.

在某些實施例中，L³包含結構：。In certain embodiments,^L3 comprises the structure: .

在某些實施例中，L⁴為視情況經取代之雜烷基連接體。在某些實施例中，雜烷基連接體經一或多個=O取代基取代。In certain embodiments,^L4 is an optionally substituted heteroalkyl linker. In certain embodiments, the heteroalkyl linker is substituted with one or more =0 substituents.

在某些實施例中，雜烷基連接體包含兩個接合在一起形成視情況經取代之碳環基環之取代基。In certain embodiments, the heteroalkyl linker comprises two substituents joined together to form an optionally substituted carbocyclyl ring.

在某些實施例中，L⁴包含結構：或其鹽，其中X為O或S。In certain embodiments,^L4 comprises the structure: or a salt thereof, wherein X is O or S.

在某些實施例中，L⁴包含結構：或其鹽，其中X為O或S。In certain embodiments,^L4 comprises the structure: or a salt thereof, wherein X is O or S.

在某些實施例中，L¹-L²-L³-L⁴包含結構：、、、、、、、、、、、、、、、、、或其鹽，其中X為O或S。In certain embodiments, L¹ -L² -L³ -L⁴ comprises the structure: , , , , , , , , , , , , , , , , , or a salt thereof, wherein X is O or S.

在某些實施例中，經修飾之寡核苷酸之TrkB配位體係選自以下各式或其鹽、溶劑合物或水合物：式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、式(XI)、式(XII)、式(XIII)、式(XIV)、式(XV)、式(XVI)、式(XVII)、式(XVIII)、式(XIX)、式(XX)， 其中： R為經修飾之寡核苷酸；且 X為S或O。In certain embodiments, the TrkB ligand of the modified oligonucleotide is selected from the following formulae or their salts, solvates or hydrates: Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), wherein: R is a modified oligonucleotide; and X is S or O.

在某些實施例中，本文所提供之化合物包含結合基團。在某些實施例中，本文所提供之寡核苷酸包含結合基團。在某些實施例中，結合基團為脂質。在某些實施例中，本文所提供之經修飾之寡核苷酸之核苷間鍵聯包含一或多種脂質。In certain embodiments, the compounds provided herein comprise a binding group. In certain embodiments, the oligonucleotides provided herein comprise a binding group. In certain embodiments, the binding group is a lipid. In certain embodiments, the internucleoside linkages of the modified oligonucleotides provided herein comprise one or more lipids.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯包含式(XXI)，或其鹽、溶劑合物或水合物：式(XXI)， 其中： Y為-C(=O)N(R^C)-或-N(R^C)C(=O)-； Q¹及Q³各自獨立地為-H、-OR⁴、配位體、連接體或脂質； Q²及Q⁴各自獨立地為鍵、、配位體、連接體或脂質； R^C獨立地為-H、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基； 每一R⁹獨立地為經取代或未經取代之雜芳基； Z¹或Z²之每一實例獨立地為鍵、C₁-C₆伸烷基或C₂-C₆伸烯基；且 每一X獨立地為O或S； 或其鹽。In certain embodiments, the internucleoside linkage of the modified oligonucleotide comprises formula (XXI), or a salt, solvate or hydrate thereof: Formula (XXI), wherein: Y is -C(=O)N(^RC )- or -N(^RC )C(=O)-;^Q1 and^Q3 are each independently -H,^-OR4 , a ligand, a linker or a lipid;^Q2 and^Q4 are each independently a bond, , ligand, linker or lipid; R^C is independently -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR 6 , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently^an oligonucleotide, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently substituted or unsubstituted heteroaryl; each R⁹ is independently substituted or unsubstituted heteroaryl; each instance of Z¹ or Z² is independently a bond, C₁ -C₆ alkylene, or C₂ -C₆ alkenylene; and each X is independently O or S; or a salt thereof.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯包含式(XXII)，或其鹽、溶劑合物或水合物：式(XXII)， 其中： R^C為-H、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之雜烷基、經取代或未經取代之芳基或經取代或未經取代之雜芳基； 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the internucleoside linkage of the modified oligonucleotide comprises formula (XXII), or a salt, solvate or hydrate thereof: Formula (XXII), wherein:^RC is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each^R2 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR6 , -N(R6), or^-SR6 ; each^R3 is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,^-OR7 , -N(^R7 ), or^-SR7;R4 and^R5 are independently oligonucleotides, or^R4 and^R5 are joined together to form a single oligonucleotide; each R R⁶ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; each R⁸ is independently substituted or unsubstituted heteroaryl ring; each R⁹ is independently substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯包含式(XXIII)，或其鹽、溶劑合物或水合物：式(XXIII)， 其中： 每一R²獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁶、-N(R⁶)或-SR⁶； 每一R³獨立地為-H、鹵素、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之炔基、-OR⁷、-N(R⁷)或-SR⁷； R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸； 每一R⁶獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁷獨立地為氫、經取代或未經取代之烷基或經取代或未經取代之雜烷基； 每一R⁸獨立地為經取代或未經取代之雜芳基環； 每一R⁹獨立地為經取代或未經取代之雜芳基環；且 每一X獨立地為O或S； 或其鹽或前藥。In certain embodiments, the internucleoside linkage of the modified oligonucleotide comprises formula (XXIII), or a salt, solvate or hydrate thereof: Formula (XXIII), wherein: each R² is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁶ , -N(R⁶ ) or -SR⁶ ; each R³ is independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR⁷ , -N(R⁷ ) or -SR⁷ ; R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; each R⁶ is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; each R⁷ is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl; each R⁸ is independently a substituted or unsubstituted heteroaryl ring; each R⁹ is independently a substituted or unsubstituted heteroaryl ring; and each X is independently O or S; or a salt or prodrug thereof.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯包含式(XXIV)，或其鹽、溶劑合物或水合物：式(XXIV). 其中： R⁴及R⁵獨立地為寡核苷酸，或R⁴及R⁵接合在一起形成單一寡核苷酸；且 每一X獨立地為O或S。In certain embodiments, the internucleoside linkage of the modified oligonucleotide comprises formula (XXIV), or a salt, solvate or hydrate thereof: Formula (XXIV). wherein: R⁴ and R⁵ are independently oligonucleotides, or R⁴ and R⁵ are joined together to form a single oligonucleotide; and each X is independently O or S.

在某些實施例中，任一前述實施例之化合物包含一或多個脂質結合基團。在某些實施例中，該一或多個脂質結合基團連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，該一或多個脂質結合基團連接至經修飾之寡核苷酸之5’端或3’端。在某些實施例中，該一或多個脂質結合基團連接至經修飾之寡核苷酸之核苷間鍵聯以及5’端或3’端。在某些實施例中，該一或多個脂質結合基團連接至經修飾之寡核苷酸之核苷間鍵聯以及5’端及3’端。在某些實施例中，該一或多種TrkB配位體連接至經修飾之寡核苷酸之5’端或3’端，或經修飾之寡核苷酸之5’端及3’端。在某些實施例中，該一或多種結合基團包含至少一種連接至經修飾之寡核苷酸之5’端或3’端或經修飾之寡核苷酸之5’端及3’端的TrkB配位體，以及至少一種脂質。在某些實施例中，該一或多種結合基團包含至少一種連接至經修飾之寡核苷酸之5’端或3’端或經修飾之寡核苷酸之5’端及3’端的TrkB配位體，以及一或多種連接至經修飾之寡核苷酸之一或多個核苷間鍵聯之脂質結合基團。在某些實施例中，經修飾之寡核苷酸包含TrkB配位體及脂質。在某些實施例中，經修飾之寡核苷酸包含一或多種TrkB配位體及一或多種脂質。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。In certain embodiments, the compound of any of the foregoing embodiments comprises one or more lipid binding groups. In certain embodiments, the one or more lipid binding groups are linked to one or more internucleoside bonds of a modified oligonucleotide. In certain embodiments, the one or more lipid binding groups are linked to the 5' end or 3' end of a modified oligonucleotide. In certain embodiments, the one or more lipid binding groups are linked to the internucleoside bonds and the 5' end or 3' end of a modified oligonucleotide. In certain embodiments, the one or more lipid binding groups are linked to the internucleoside bonds and the 5' end and 3' end of a modified oligonucleotide. In certain embodiments, the one or more TrkB ligands are linked to the 5' end or 3' end of a modified oligonucleotide, or to the 5' end and 3' end of a modified oligonucleotide. In certain embodiments, the one or more binding groups comprise at least one TrkB ligand linked to the 5' end or 3' end or both of the modified oligonucleotide, and at least one lipid. In certain embodiments, the one or more binding groups comprise at least one TrkB ligand linked to the 5' end or 3' end or both of the modified oligonucleotide, and one or more lipid binding groups linked to one or more internucleoside bonds of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises a TrkB ligand and a lipid. In certain embodiments, the modified oligonucleotide comprises one or more TrkB ligands and one or more lipids. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide.

在某些實施例中，任一前述實施例之化合物包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸之一或多個核苷間鍵聯。在某些實施例中，經修飾之寡核苷酸為第二經修飾之寡核苷酸或有義寡核苷酸。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₇烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₈烴鏈。在某些實施例中，該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₂₂烴鏈。In certain embodiments, the compound of any of the foregoing embodiments comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the substituted or unsubstituted alkyl or alkenyl group is linked to the internucleoside linkage of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to one or more internucleoside linkages of the modified oligonucleotide. In certain embodiments, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated C₄ -C₃₀ hydrocarbon chain. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₅ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₆ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₇ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain saturated or unsaturated C₁₈ hydrocarbon chains. In certain embodiments, the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated_C22 hydrocarbon chain.

在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，經取代或未經取代之烷基或烯基連接至經修飾之寡核苷酸(例如第二經修飾之寡核苷酸或有義寡核苷酸)之核苷間鍵聯。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之末端(例如5'端及/或3'端) 10個位置內(例如8個位置內、6個位置內、5個位置內、4個位置內、3個位置內、2個位置內)的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端5個位置內的核苷之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端5個位置內的核苷之間。In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, a substituted or unsubstituted alkyl or alkenyl group is linked to an internucleoside linkage of a modified oligonucleotide (e.g., a second modified oligonucleotide or a sense oligonucleotide). In certain embodiments, the internucleoside linkage is between nucleosides within 10 positions (e.g., within 8 positions, within 6 positions, within 5 positions, within 4 positions, within 3 positions, within 2 positions) of the end (e.g., the 5' end and/or the 3' end) of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is between nucleosides within 5 positions of the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkages are between nucleosides within 5 positions from the 3' end of the modified oligonucleotide.

在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之5'端的2位與3位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間、7位與8位之間、8位與9位之間、9位與10位之間、10位與11位之間、11位與12位之間、12位與13位之間或13位與14位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的1位與2位之間、2位與3位之間、3位與4位之間、4位與5位之間、5位與6位之間、6位與7位之間或7位與8位之間。在某些實施例中，核苷間鍵聯位於距經修飾之寡核苷酸之3'端的2位與3位之間。In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, 7 and 8, 8 and 9, 9 and 10, 10 and 11, 11 and 12, 12 and 13, or 13 and 14 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between 1 and 2, 2 and 3, 3 and 4, 4 and 5, 5 and 6, 6 and 7, or 7 and 8 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 5' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, between positions 7 and 8, between positions 8 and 9, between positions 9 and 10, between positions 10 and 11, between positions 11 and 12, between positions 12 and 13, or between positions 13 and 14 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 1 and 2, between positions 2 and 3, between positions 3 and 4, between positions 4 and 5, between positions 5 and 6, between positions 6 and 7, or between positions 7 and 8 from the 3' end of the modified oligonucleotide. In certain embodiments, the internucleoside linkage is located between positions 2 and 3 from the 3' end of the modified oligonucleotide.

在某些實施例中，經修飾之寡核苷酸之核苷間鍵聯係選自式XXI-式XXIV中之任一者。靶核酸及靶區域In certain embodiments, the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXI to Formula XXIV.Target Nucleic Acid and Target Region

在某些實施例中，本文所闡述之化合物包含含有與靶核酸互補之區域的寡核苷酸或由其組成。在某些實施例中，靶核酸為內源性RNA分子。在某些實施例中，靶核酸編碼蛋白質。在某些實施例中，靶核酸係非編碼的。在某些此類實施例中，靶核酸係選自mRNA及前mRNA，包括內含子區、外顯子區及非轉譯區。在某些實施例中，靶RNA為mRNA。在某些實施例中，靶核酸為前mRNA。在某些此類實施例中，靶區域完全位於外顯子內。在某些此類實施例中，靶區域完全位於內含子內。在某些實施例中，靶區域跨內含子/外顯子接點。在某些實施例中，靶區域至少50%位於內含子內。In certain embodiments, the compounds described herein comprise or consist of oligonucleotides containing regions complementary to the target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain embodiments, the target nucleic acid is non-coding. In certain such embodiments, the target nucleic acid is selected from mRNA and pre-mRNA, including intronic regions, exonic regions, and non-translational regions. In certain embodiments, the target RNA is mRNA. In certain embodiments, the target nucleic acid is pre-mRNA. In certain such embodiments, the target region is completely within the exon. In certain such embodiments, the target region is completely within the intron. In certain embodiments, the target region spans an intron/exon junction. In certain embodiments, at least 50% of the target region is located within the intron.

在某些實施例中，本文所揭示之化合物與LRRK2核酸雜交。最常見的雜交機制涉及核酸分子之互補核鹼基之間的氫鍵結。雜交可在不同條件下發生。雜交條件依賴於序列，且由待雜交核酸分子之性質及組成決定。確定序列是否與靶核酸特異性地雜交之方法為此項技術中所熟知。在某些實施例中，本文所提供之化合物與LRRK2核酸特異性地雜交。In certain embodiments, the compounds disclosed herein hybridize with LRRK2 nucleic acids. The most common hybridization mechanism involves hydrogen bonding between complementary nucleobases of nucleic acid molecules. Hybridization can occur under different conditions. Hybridization conditions are sequence dependent and are determined by the nature and composition of the nucleic acid molecules to be hybridized. Methods for determining whether a sequence specifically hybridizes with a target nucleic acid are well known in the art. In certain embodiments, the compounds provided herein specifically hybridize with LRRK2 nucleic acids.

編碼LRRK2之核苷酸序列包括(但不限於)以下：GenBank登錄號NM_198578.4 (以SEQ ID NO: 1併入本文中)，及NG_011709.2之核苷酸5002至149290 (以SEQ ID NO: 2併入本文中)。互補性Nucleotide sequences encoding LRRK2 include, but are not limited to, the following: GenBank Accession No. NM_198578.4 (incorporated herein as SEQ ID NO: 1), and nucleotides 5002 to 149290 of NG_011709.2 (incorporated herein as SEQ ID NO: 2).

本文所提供之寡核苷酸可與特定核酸、靶區域、寡核苷酸或其部分具有確定之互補性百分比。非互補核鹼基係可容忍的，前提條件為寡核苷酸仍能夠與核酸、寡核苷酸或其部分特異性地雜交。在某些實施例中，本文所提供之寡核苷酸或其指定部分與靶核酸、靶區域、寡核苷酸或其指定部分至少或高達70%、80%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%互補。在某些實施例中，本文所提供之寡核苷酸或其指定部分與靶核酸、靶區域、寡核苷酸或其指定部分互補70%至75%、75%至80%、80%至85%、85%至90%、90%至95%、95%至100%，或該等範圍之間的任何數值。可使用常規方法來確定寡核苷酸與靶核酸、靶區域、寡核苷酸或其指定部分之互補性百分比。舉例而言，寡核苷酸之20個核鹼基中有18個與靶區域互補，且因此將特異性地雜交之寡核苷酸將代表90%之互補性。在該實例中，其餘非互補核鹼基可與互補核鹼基成簇或間雜排列，且不需要彼此鄰接或與互補核鹼基鄰接。因此，具有4個非互補核鹼基(側翼為與靶核酸完全互補之兩個區域)之長度為18個核鹼基之寡核苷酸與靶核酸之總互補性為77.8%。寡核苷酸與靶核酸、靶區域、寡核苷酸或其指定部分之區域的互補性百分比可使用此項技術中已知之BLAST程式(基本局部比對搜索工具)常規地確定。在某些實施例中，本文所闡述之寡核苷酸或其指定部分與靶核酸、靶區域、寡核苷酸或其指定部分完全互補(亦即100%互補)。舉例而言，寡核苷酸可與靶核酸、靶區域、寡核苷酸或其指定部分完全互補。如本文所用，「完全互補」意指寡核苷酸之每一核鹼基與靶核酸、靶區域、寡核苷酸或其指定部分之相應核鹼基互補。舉例而言，20個核鹼基之寡核苷酸與長為400個核鹼基之靶序列完全互補，只要靶核酸之相應20個核鹼基部分與化合物完全互補即可。針對第一核酸及/或第二核酸之指定部分亦可使用「完全互補」。舉例而言，30個核鹼基之寡核苷酸之20個核鹼基部分可與長為400個核鹼基之靶序列之20個核鹼基區域「完全互補」。若靶序列具有20個核鹼基部分，其中每一核鹼基與30個核鹼基化合物之20個相應核鹼基部分互補，則該化合物之該20個核鹼基部分與靶序列完全互補。同時，整個30個核鹼基化合物可與靶序列完全互補或可不完全互補，此取決於該化合物之其餘10個核鹼基是否亦與靶序列互補。Oligonucleotides provided herein can have a defined complementarity percentage with a specific nucleic acid, target region, oligonucleotide or portion thereof. Non-complementary bases are tolerated provided that the oligonucleotide is still able to hybridize specifically with the nucleic acid, oligonucleotide or portion thereof. In certain embodiments, the oligonucleotides provided herein or a specified portion thereof are at least or up to 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% complementary with a target nucleic acid, target region, oligonucleotide or portion thereof. In certain embodiments, the oligonucleotides provided herein or their designated portions are complementary to the target nucleic acid, target region, oligonucleotide or its designated portion by 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or any value between these ranges. Conventional methods can be used to determine the complementarity percentage of the oligonucleotide and the target nucleic acid, target region, oligonucleotide or its designated portion. For example, 18 of the 20 nucleobases of the oligonucleotide are complementary to the target region, and therefore the oligonucleotides specifically hybridized will represent 90% complementarity. In this example, the remaining non-complementary nucleobases can be clustered or interspersed with complementary nucleobases, and do not need to be adjacent to each other or adjacent to complementary nucleobases. Thus, an oligonucleotide of 18 nucleobases in length having 4 non-complementary nucleobases flanked by two regions that are completely complementary to the target nucleic acid has a total complementarity of 77.8% with the target nucleic acid. The percent complementarity of an oligonucleotide with a target nucleic acid, a target region, a region of an oligonucleotide or a designated portion thereof can be routinely determined using the BLAST program (Basic Local Alignment Search Tool) known in the art. In certain embodiments, an oligonucleotide or a designated portion thereof described herein is completely complementary (i.e., 100% complementary) to a target nucleic acid, a target region, an oligonucleotide or a designated portion thereof. For example, an oligonucleotide can be completely complementary to a target nucleic acid, a target region, an oligonucleotide or a designated portion thereof. As used herein, "completely complementary" means that each nucleobase of an oligonucleotide is complementary to the corresponding nucleobase of a target nucleic acid, a target region, an oligonucleotide or a designated portion thereof. For example, a 20 nucleobase oligonucleotide is fully complementary to a target sequence that is 400 nucleobases in length as long as the corresponding 20 nucleobase portion of the target nucleic acid is fully complementary to the compound. "Fully complementary" may also be used with respect to a specified portion of the first nucleic acid and/or the second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase oligonucleotide may be "fully complementary" to a 20 nucleobase region of a target sequence that is 400 nucleobases in length. If the target sequence has a 20 nucleobase portion, each of which is complementary to the 20 corresponding nucleobase portions of a 30 nucleobase compound, then the 20 nucleobase portion of the compound is fully complementary to the target sequence. At the same time, the entire 30-nucleotide base compound may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleotides of the compound are also complementary to the target sequence.

在某些實施例中，本文所闡述之寡核苷酸相對於靶核酸、靶區域、寡核苷酸或其指定部分包含一或多個失配核鹼基。在某些實施例中，本文所闡述之長度為或高達12、13、14、15、16、17、18、19、20、21、22或23個核鹼基之寡核苷酸相對於靶核酸或其指定部分包含不超過4個、不超過3個、不超過2個或不超過1個非互補核鹼基。在某些實施例中，本文所闡述之長度為或高達14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核鹼基之寡核苷酸相對於靶核酸、靶區域、寡核苷酸或其指定部分包含不超過6個、不超過5個、不超過4個、不超過3個、不超過2個或不超過1個非互補核鹼基。在某些實施例中，失配位於距寡核苷酸5’端之1位、2位、3位、4位、5位、6位、7位、8位、9位、10位、11位、12位、13位或14位處。在某些實施例中，失配位於距寡核苷酸3’端之1位、2位、3位、4位、5位、6位、7位、8位、9位、10位、11位或12位、13位或14位處。在某些實施例中，失配與靶核酸上之相應核鹼基形成搖擺鹼基對。舉例而言，在某些實施例中，失配形成選自以下之搖擺鹼基對：次黃嘌呤(肌苷核鹼基)與尿嘧啶(I:U鹼基對)；鳥嘌呤與尿嘧啶(G:U鹼基對)；次黃嘌呤與腺嘌呤(I:A鹼基對)；及次黃嘌呤與胞嘧啶(I:C鹼基對)。因此，在某些實施例中，寡核苷酸上之失配核鹼基包含次黃嘌呤、鳥嘌呤或尿嘧啶。In certain embodiments, the oligonucleotides described herein comprise one or more mismatched nucleobases relative to the target nucleic acid, target region, oligonucleotide, or a designated portion thereof. In certain embodiments, the oligonucleotides described herein having a length of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleobases or more comprise no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase relative to the target nucleic acid or a designated portion thereof. In certain embodiments, the oligonucleotides described herein of length or up to 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase relative to the target nucleic acid, target region, oligonucleotide, or a designated portion thereof. In certain embodiments, the mismatch is located at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 from the 5' end of the oligonucleotide. In certain embodiments, the mismatch is located at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 13, or 14 from the 3' end of the oligonucleotide. In certain embodiments, the mismatch forms a dangling base pair with the corresponding nucleobase on the target nucleic acid. For example, in certain embodiments, the mismatch forms a dangling base pair selected from the following: hypoxanthine (inosine nucleobase) and uracil (I:U base pair); guanine and uracil (G:U base pair); hypoxanthine and adenine (I:A base pair); and hypoxanthine and cytosine (I:C base pair). Thus, in certain embodiments, the mismatched nucleobase on the oligonucleotide comprises hypoxanthine, guanine, or uracil.

在某些實施例中，本文所闡述之寡核苷酸可與核酸之一部分互補。如本文所用，「部分」係指核酸區域內確定數量之鄰接核鹼基。「部分」亦可指寡核苷酸之確定數量之鄰接核鹼基。在某些實施例中，寡核苷酸與核酸之至少8個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少9個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少10個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少11個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少12個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少13個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少14個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少15個核鹼基之部分互補。在某些實施例中，寡核苷酸與核酸之至少16個核鹼基之部分互補。亦考慮與核酸之至少9、10、17、18、19、20、21、22、23或更多個核鹼基之部分互補之寡核苷酸，或由該等值中之任兩者界定之範圍。在某些實施例中，寡核苷酸為反義寡核苷酸。在某些實施例中，將反義寡核苷酸之一部分與靶核酸之等長部分進行比較。在某些實施例中，將8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核鹼基之部分與靶核酸之等長部分進行比較。在某些實施例中，寡核苷酸為有義寡核苷酸。在某些實施例中，將有義寡核苷酸之一部分與反義寡核苷酸之等長部分進行比較。在某些實施例中，將有義寡核苷酸之8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核鹼基之部分與反義寡核苷酸之等長部分進行比較。一致性In certain embodiments, the oligonucleotides described herein may complement a portion of a nucleic acid. As used herein, "portion" refers to a defined number of adjacent nucleobases within a region of a nucleic acid. "Portion" may also refer to a defined number of adjacent nucleobases of an oligonucleotide. In certain embodiments, an oligonucleotide complements a portion of at least 8 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 9 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 10 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 11 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 12 nucleobases of a nucleic acid. In certain embodiments, an oligonucleotide complements a portion of at least 13 nucleobases of a nucleic acid. In some embodiments, the oligonucleotide complements a portion of at least 14 nucleobases of a nucleic acid. In some embodiments, the oligonucleotide complements a portion of at least 15 nucleobases of a nucleic acid. In some embodiments, the oligonucleotide complements a portion of at least 16 nucleobases of a nucleic acid. Oligonucleotides that complement a portion of at least 9, 10, 17, 18, 19, 20, 21, 22, 23 or more nucleobases of a nucleic acid are also contemplated, or ranges defined by any two of the equivalent values. In some embodiments, the oligonucleotide is an antisense oligonucleotide. In some embodiments, a portion of an antisense oligonucleotide is compared to an equal length portion of a target nucleic acid. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases is compared to an equal length portion of a target nucleic acid. In some embodiments, the oligonucleotide is a sense oligonucleotide. In some embodiments, a portion of a sense oligonucleotide is compared to an equal length portion of an antisense oligonucleotide. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases of a sense oligonucleotide is compared to an equal length portion of an antisense oligonucleotide.Consistency

本文所提供之寡核苷酸亦可與特定核酸、靶區域、寡核苷酸或其指定部分具有確定之一致性百分比。如本文所用，若寡核苷酸具有相同的核鹼基配對能力，則其與本文所揭示之序列一致。舉例而言，含有胸苷代替所揭示RNA序列中之尿嘧啶之DNA將視為與該RNA序列一致，此乃因尿嘧啶及胸苷二者均與腺嘌呤配對。亦考慮本文所闡述化合物之縮短及加長形式，以及相對於本文所提供之化合物具有不同鹼基之化合物。不同鹼基可彼此毗鄰，或分散在整個化合物中。根據相對於與寡核苷酸相比較之序列具有相同鹼基配對之鹼基數，計算寡核苷酸之一致性百分比。在某些實施例中，本文所闡述之寡核苷酸或其部分與本文所揭示之核酸、寡核苷酸或其一部分中之一或多者之一致性為或至少為70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%。在某些實施例中，本文所闡述之寡核苷酸與特定核酸或寡核苷酸或其部分約70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致，或此等值之間的任何百分比。The oligonucleotides provided herein may also have a determined percent identity with a specific nucleic acid, a target region, an oligonucleotide or a designated portion thereof. As used herein, if an oligonucleotide has the same nucleobase pairing ability, it is consistent with the sequence disclosed herein. For example, a DNA containing thymidine instead of uracil in the disclosed RNA sequence will be considered consistent with the RNA sequence, because both uracil and thymidine are paired with adenine. Shortened and elongated forms of the compounds described herein, as well as compounds with different bases relative to the compounds provided herein are also considered. Different bases may be adjacent to each other or dispersed throughout the compound. The percent identity of the oligonucleotide is calculated based on the number of bases with the same base pairing relative to the sequence compared with the oligonucleotide. In certain embodiments, the oligonucleotides described herein or portions thereof are or are at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to one or more of the nucleic acids, oligonucleotides, or portions thereof disclosed herein. In certain embodiments, the oligonucleotides described herein are about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a particular nucleic acid or oligonucleotide, or portion thereof, or any percentage in between these values.

在某些實施例中，寡核苷酸可具有一或多個失配核鹼基。在某些此類實施例中，失配位於距寡核苷酸5’端之1位、2位、3位、4位、5位、6位、7位、8位、9位、10位、11位、12位、13位或14位處。在某些此類實施例中，失配位於距寡核苷酸3’端之1位、2位、3位、4位、5位、6位、7位、8位、9位、10位、11位或12位、13位或14位處。在某些實施例中，將寡核苷酸之一部分與靶核酸之等長部分進行比較。在某些實施例中，將8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核鹼基之部分與靶核酸之等長部分進行比較。在某些實施例中，寡核苷酸為有義寡核苷酸。在某些實施例中，將有義寡核苷酸之一部分與靶核酸之等長部分進行比較。在某些實施例中，將8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24或25個核鹼基之部分與靶核酸之等長部分進行比較。醫藥組合物及調配物In some embodiments, an oligonucleotide may have one or more mismatched nucleobases. In some such embodiments, the mismatch is at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 positions from the 5' end of the oligonucleotide. In some such embodiments, the mismatch is at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 positions from the 3' end of the oligonucleotide. In some embodiments, a portion of an oligonucleotide is compared to an equal length portion of a target nucleic acid. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases is compared to an equal length portion of a target nucleic acid. In some embodiments, the oligonucleotide is a sense oligonucleotide. In some embodiments, a portion of a sense oligonucleotide is compared to an equal length portion of a target nucleic acid. In some embodiments, a portion of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases is compared to an equal length portion of a target nucleic acid.Pharmaceutical compositions and formulations

本文所闡述之化合物可與醫藥學上可接受之活性或惰性物質混合以供製備醫藥組合物或調配物。用於調配醫藥組合物之組合物及方法取決於多種準則，包括(但不限於)投與途徑、疾病程度或欲投與之劑量。某些實施例提供包含一或多種化合物或其鹽之醫藥組合物。在某些實施例中，化合物為反義寡核苷酸。在某些實施例中，化合物為寡聚化合物。在某些實施例中，化合物包含一或多種經修飾之寡核苷酸或由其組成。在某些此類實施例中，醫藥組合物包含一或多種化合物及適宜的醫藥學上可接受之稀釋劑或載劑。在某些實施例中，醫藥組合物包含一或多種化合物及無菌鹽水溶液。在某些實施例中，此醫藥組合物係由一種化合物及無菌鹽水溶液組成。在某些實施例中，無菌鹽水為醫藥級鹽水。在某些實施例中，醫藥組合物包含一或多種化合物及無菌水。在某些實施例中，醫藥組合物係由一種化合物及無菌水組成。在某些實施例中，無菌水為醫藥級水。在某些實施例中，醫藥組合物包含一或多種化合物及磷酸鹽緩衝鹽水(PBS)。在某些實施例中，醫藥組合物係由一種化合物及無菌PBS組成。在某些實施例中，無菌PBS為醫藥級PBS。The compounds described herein can be mixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. The compositions and methods for preparing pharmaceutical compositions depend on a variety of criteria, including, but not limited to, the route of administration, the extent of the disease, or the dose to be administered. Certain embodiments provide pharmaceutical compositions comprising one or more compounds or their salts. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or is composed of one or more modified oligonucleotides. In certain such embodiments, the pharmaceutical composition comprises one or more compounds and a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutical composition comprises one or more compounds and a sterile saline solution. In some embodiments, the pharmaceutical composition is composed of a compound and a sterile saline solution. In some embodiments, the sterile saline is pharmaceutical grade saline. In some embodiments, the pharmaceutical composition comprises one or more compounds and sterile water. In some embodiments, the pharmaceutical composition is composed of a compound and sterile water. In some embodiments, the sterile water is pharmaceutical grade water. In some embodiments, the pharmaceutical composition comprises one or more compounds and phosphate buffered saline (PBS). In some embodiments, the pharmaceutical composition is composed of a compound and sterile PBS. In some embodiments, the sterile PBS is pharmaceutical grade PBS.

可藉由將本文所闡述之靶向LRRK2之化合物與適宜的醫藥學上可接受之稀釋劑或載劑組合，將該化合物用於醫藥組合物中。在某些實施例中，醫藥學上可接受之稀釋劑為水，諸如適於注射之無菌水。因此，在一個實施例中，本文所闡述之方法中採用包含靶向LRRK2之化合物及醫藥學上可接受之稀釋劑的醫藥組合物。在某些實施例中，醫藥學上可接受之稀釋劑為水。在某些實施例中，化合物包含本文所提供之一或多種經修飾之寡核苷酸或由其組成。The compounds targeting LRRK2 described herein can be used in pharmaceutical compositions by combining them with a suitable pharmaceutically acceptable diluent or carrier. In certain embodiments, the pharmaceutically acceptable diluent is water, such as sterile water suitable for injection. Therefore, in one embodiment, a pharmaceutical composition comprising a compound targeting LRRK2 and a pharmaceutically acceptable diluent is used in the methods described herein. In certain embodiments, the pharmaceutically acceptable diluent is water. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides provided herein.

包含本文所提供化合物之醫藥組合物涵蓋任何醫藥學上可接受之鹽、酯或此等酯之鹽，或在投與給動物、包括人類時能夠(直接或間接)提供其生物活性代謝物或殘餘物之任何其他寡核苷酸。在某些實施例中，化合物為反義寡核苷酸。在某些實施例中，化合物為寡聚化合物。在某些實施例中，化合物包含一或多種經修飾之寡核苷酸或由其組成。因此，舉例而言，本揭示案亦係關於化合物之醫藥學上可接受之鹽、前藥、此等前藥之醫藥學上可接受之鹽及其他生物等效形式。適宜的醫藥學上可接受之鹽包括(但不限於)鈉鹽及鉀鹽。前藥可包括在化合物之一端或兩端併入額外核苷，其在體內由內源性核酸酶裂解，形成活性化合物。在某些實施例中，化合物或組合物進一步包含醫藥學上可接受之載劑或稀釋劑。實例Pharmaceutical compositions comprising the compounds provided herein encompass any pharmaceutically acceptable salt, ester, or salt of such esters, or any other oligonucleotide capable of providing (directly or indirectly) its biologically active metabolites or residues when administered to animals, including humans. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides. Therefore, for example, the present disclosure also relates to pharmaceutically acceptable salts, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalent forms of the compound. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium salts and potassium salts. Prodrugs may include additional nucleosides incorporated into one or both ends of the compound, which are cleaved by endogenous nucleases invivo to form active compounds. In certain embodiments, the compound or composition further comprises a pharmaceutically acceptable carrier or diluent.

以下實例闡述鑑別靶向LRRK2之前導化合物之過程。某些化合物認定為具有高效能及耐受性。The following examples illustrate the process of identifying lead compounds targeting LRRK2. Certain compounds were identified as having high potency and tolerability.

以下實例僅用於闡釋本文所闡述之化合物，而不意欲對其加以限制。本申請隨附之以下實例及相關序列表可將序列鑑別為「RNA」或「DNA」；然而，如本文所揭示，彼等序列可經化學修飾之任何組合修飾。熟習此項技術者將容易地瞭解，在某些情況下，將序列命名為「RNA」或「DNA」係任意的。舉例而言，可將包含含有2’-OH糖部分及胸腺嘧啶鹼基之核苷的寡核苷酸描述為具有經修飾之糖(2’-OH代替DNA之天然2’-H)的DNA或描述為具有經修飾之鹼基(甲基化尿嘧啶代替RNA之天然尿嘧啶)的RNA。因此，本文所提供之核酸序列(包括(但不限於)序列表中之彼等核酸序列)意欲涵蓋含有天然或經修飾之RNA及/或DNA之任何組合的核酸，包括(但不限於)具有經修飾之核鹼基的此等核酸。The following examples are intended only to illustrate the compounds described herein and are not intended to be limiting. The following examples and associated sequence listings accompanying this application may identify sequences as "RNA" or "DNA"; however, as disclosed herein, those sequences may be modified by any combination of chemical modifications. Those skilled in the art will readily appreciate that in certain circumstances, the naming of sequences as "RNA" or "DNA" is arbitrary. For example, an oligonucleotide comprising a nucleoside containing a 2'-OH sugar moiety and a thymine base may be described as a DNA with a modified sugar (2'-OH instead of the natural 2'-H of DNA) or as an RNA with a modified base (methylated uracil instead of the natural uracil of RNA). Therefore, the nucleic acid sequences provided herein (including but not limited to those in the sequence listing) are intended to encompass nucleic acids containing any combination of native or modified RNA and/or DNA, including but not limited to such nucleic acids with modified nucleobases.

本申請案中所引用之每一參考文獻均係以全文引用的方式併入本文中。表1化學命名法縮寫結構『m』2’-O-甲基糖修飾(例如mA、mG、mC、mU)『f』2’-F糖修飾(例如fA、fG、fC、fU)『*』硫代磷酸酯核苷間鍵聯『.』磷酸酯核苷間鍵聯『dQ』反向無鹼基去氧核糖『v』5’-乙烯基膦酸酯修飾『e』5’-伸乙基膦酸酯修飾『5’-L』5’TrkB配位體『3’-L』3’TrkB配位體『FIII』TrkB配位體式III，其中X為S『FIV』TrkB配位體式IV，其中X為S『FVI』TrkB配位體式VI，其中X為S『FVII』TrkB配位體式VII，其中X為S『FX』TrkB配位體式FX，其中X為S『FXX』TrkB配位體式XX，其中X為S『fUëmA』含有二核苷酸[fUmA]之寡核苷酸，其具有與脂質之醯胺核苷間鍵聯；脂質式(XXIV)，其中X為Ot63'-硫醇改質劑C6 S-S (亦即1-O-二甲氧基三苯甲基-己基-二硫化物,1'-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺)表2化合物序列及SEQ ID NO: 1上之靶向位置化合物編號SEQ ID NO:1起始位點SEQ ID NO:1終止位點反義序列SEQ ID NO:有義序列SEQ ID NO:(5’-3’)(5’-3’)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表3化合物化學化合物5’-L經修飾之股(5’-3’)3’-LRef ID NO:SEQ ID 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reference cited in this application is incorporated herein by reference in its entirety.Table 1Chemical NomenclatureAbbreviationStructure 『m』 2'-O-methyl sugar modifications (e.g. mA, mG, mC, mU) 『f』 2'-F sugar modification (e.g. fA, fG, fC, fU) 『*』 Phosphorothioate internucleoside bonds 『.』 Phosphate internucleoside bonds 『dQ』 Reverse abasic deoxyribose 『v』 5'-Vinylphosphonate modification 『e』 5'-Ethylenephosphonate modification 『5'-L』 5'TrkB ligand 『3'-L』 3'TrkB ligand 『FIII』 TrkB ligand formula III, where X is S 『FIV』 TrkB ligand formula IV, where X is S 『FVI』 TrkB ligand formula VI, where X is S 『FVII』 TrkB ligand formula VII, where X is S 『FX』 The TrkB ligand has the formula FX, where X is S 『FXX』 The TrkB ligand has the formula XX, where X is S 『fUëmA』 An oligonucleotide containing the dinucleotide [fUmA] having an amide internucleoside linkage to a lipid; the lipid having the formula (XXIV) wherein X is O t6 3'-Mercapto Modifier C6 SS (i.e. 1-O-dimethoxytrityl-hexyl-disulfide, 1'-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamidite)Table 2Compound sequences and target positions on SEQ ID NO: 1Compound No.SEQ ID NO:1start siteSEQ ID NO:1stop siteAntisense sequenceSEQ ID NO:Sense sequenceSEQ ID NO:(5'-3')(5'-3') RD3693 1519 1541 AGAUGAUUUAGCAUUUUACAGCC 11 GCUGUAAAAUGCUAAAUCAUCU 45 RD3694 1946 1968 UCCUAUAAGACUUAAACCCAGAC 12 UCUGGGUUUAAGUCUUAUAGGA 46 RD3695 2033 2055 AUCCUUAAAUCGGUAUAAGCUGG 13 CAGCUUAUACCGAUUUAAGGAU 47 RD3696 2301 2323 UAAGCAAGCAUUCAACCAUGAUG 14 AUCAUGGUUGAAUGCUUGCUUA 48 RD3697 2435 2457 UGCUUUUCGUACAUCUUGUUCAC 15 UGAACAAGAUGUACGAAAAGCA 49 RD3698 2657 2679 UAUCUGAUAUCUGAUCACCAUUC 16 AAUGGUGAUCAGAUAUCAGAUA 50 RD3699 2659 2681 UUCAUCUGAUAUCUGAUCACCAU 17 UGGUGAUCAGAUAUCAGAUGA 51 RD3700 3101 3123 AUCUCUUAGUUCAUUUGCUGAAA 18 UUCAGCAAAUGAACUAAGAGAU 52 RD3701 3104 3126 AAUAUCUCUUAGUUCAUUUGCUG 19 AGCAAAUGAACUAAGAGAUAUU 53 RD3702 3203 3225 UAGCUGUUGUGGAAAGCUCGUGA 20 CACGAGCUUUCCACAACAGCUA 54 RD3703 3244 3266 UUGUGCAAGUCCAAAUGUGUCAA twenty one UGACACAUUUGGACUUGCACAA 55 RD3704 4370 4392 AUAGACAGCAAGGUACAAUGCUC twenty two AGCAUUGUACCUUGCUGUCUAU 56 RD3705 5380 5402 UCUAAGACUUCAGAUCCUACCAG twenty three UGGUAGGAUCUGAAGUCUUAGA 57 RD3706 7023 7045 UCAAACACAUCAAUGGAGUACUG twenty four AGUACUCCAUUGAUGUGUUUGA 58 RD4067 1516 1538 UGAUUUAGCAUUUUACAGCCACU 25 GUGGCUGUAAAAUGCUAAAUCA 59 RD4068 1518 1540 UAUGAUUUAGCAUUUUACAGCCA 26 GGCUGUAAAAUGCUAAAUCAUA 60 RD4069 1947 1969 AUCCUAUAAGACUUAAACCCAGA 27 CUGGGUUUAAGUCUUAUAGGAU 61 RD4070 2304 2326 AUAGAAGCAAGCAUUCAACCAUG 28 AUGGUUGAAUGCUUGCUUCUAU 62 RD4071 2305 2327 AAUAGAAGCAAGCAUUCAACCAU 29 UGGUUGAAUGCUUGCUUCUAUU 63 RD4072 2662 2684 UUUUUCAUCUGAUAUCUGAUCAC 30 UGAUCAGAUAUCAGAUGAAAAA 64 RD4073 3010 3032 UAUUGAAGUUUUGAUGACCUGAG 31 UCAGGUCAUCAAAACUUCAAUA 65 RD4074 3100 3122 UCUCUUAGUUCAUUUGCUGAAAG 32 UUUCAGCAAAUGAACUAAGAGA 66 RD4075 3199 3221 UGUUGUGGAAAGCUCGUGAGUGC 33 CACUCACGAGCUUUCCACAACA 67 RD4076 3202 3224 AGCUGUUGUGGAAAGCUCGUGAG 34 UCACGAGCUUUCCACAACAGCU 68 RD4077 3204 3226 AUAGCUGUUGUGGAAAGCUCGUG 35 ACGAGCUUUCCACAACAGCUAU 69 RD4078 3929 3951 AGAUGUCAGAUUUUCAAGACAGC 36 CUGUCUUGAAAAUCUGACAUCU 70 RD4079 4367 4389 UACAGCAAGGUACAAUGCUCGCU 37 GCGAGCAUUGUACCUUGCUGUA 71 RD4080 4369 4391 UAGACAGCAAGGUACAAUGCUCG 38 GAGCAUUGUACCUUGCUGUCUA 72 RD4081 4577 4599 UACAAAGUGGUAAUCUCGUAUGG 39 CAUACGAGAUUACCACUUUGUA 73 RD4082 5289 5311 UUCGUUCUCUCCCUGAAAGCAUG 40 AUGCUUUCAGGGAGAGAACGAA 74 RD4083 5762 5784 AAACUCUGGAGCUUGUUCAAGUU 41 ACUUGAACAAGCUCCAGAGUUU 75 RD4084 6194 6216 UAUUCUACAGCAGUACUGAGCAA 42 UGCUCAGUACUGCUGUAGAAUA 76 RD4085 6239 6261 UUCAGGUGCACGAAACCCUGGUG 43 ACCAGGGUUUCGUGCACCUGAA 77 RD4086 6571 6593 UCAACAAUUACGUUUUUAGGUGA 44 CACCUAAAAACGUAAUUGUUGA 78 RD4113 1519 1541 AGAUGAUUUAGCAUUUUACAGCC 11 GCUGUAAAAUGCUAAAUCAUCU 45 RD4116 2033 2055 AUCCUUAAAUCGGUAUAAGCUGG 13 CAGCUUAUACCGAUUUAAGGAU 47 RD4134 1519 1541 AGAUGAUUUAGCAUUUUACAGCC 11 GCUGUAAAAUGCUAAAUCAUCU 45 RD4135 2033 2055 AUCCUUAAAUCGGUAUAAGCUGG 13 CAGCUUAUACCGAUUUAAGGAU 47 RD4270 3199 3221 UGUUGUGGAAAGCUCGUGAGUGC 33 CACUCACGAGCUUUCCACAACA 67 RD4271 3199 3221 UGUUGUGGAAAGCUCGUGAGUGC 33 CACUCACGAGCUUUCCACAACA 67 RD4275 1519 1541 AGAUGAUUUAGCAUUUUACAGCC 11 GCUGUAAAAUGCUAAAUCAUCUC 79 RD4277 2033 2055 AUCCUUAAAUCGGUAUAAGCUGG 13 CAGCUUAUACCGAUUUAAGGAUC 80 RD4279 3199 3221 UGUUGUGGAAAGCUCGUGAGUGC 33 CACUCACGAGCUUUCCACAACAC 81 RD4416 1516 1538 UGAUUUAGCAUUUUACAGCCACU 25 GUGGCUGUAAAAUGCUAAAUCAC 82 RD4314 957 979 AAUUACCUAAUGUAAGCCUAUGG 83 CAUAGGCUUACAUUAGGUAAUU 90 RD4315 1902 1924 UAUACAUCUGCAGUGUGUGAAGC 84 CUUCACACACUGCAGAUGUAUA 91 RD4316 2482 2504 AGCAAGCUGAUGAUCUGGCUGUC 85 ACAGCCAGAUCAUCAGCUUGCU 92 RD4317 3004 3026 AGUUUUGAUGACCUGAGUGAAUC 86 AUUCACUCAGGUCAUCAAAACU 93 RD4318 3051 3073 UAGAAGCCAGAGAAGAAAUGCUG 87 AGCAUUUCUUCUCUGGCUUCUA 94 RD4319 4421 4443 UAAGAGCCAAGGCUUCAUGGCAU 88 UGCCAUGAAGCCUUGGCUCUUA 95 RD4320 6501 6523 UAAAGACCUGGGCAGAAGUAGGC 89 CCUACUUCUGCCCAGGUCUUUA 96 RD4335 1516 1538 UGAUUUAGCAUUUUACAGCCACU 25 GUGGCUGUAAAAUGCUAAAUCAC 82 RD4362 1516 1538 UGAUUUAGCAUUUUACAGCCACU 25 GUGGCUGUAAAAUGCUAAAUCAC 82 RD4415 1516 1538 UGAUUUAGCAUUUUACAGCCACU 25 GUGGCUGUAAAAUGCUAAAUCAC 82 RD4361 1516 1538 UGAUUUAGCAUUUUACAGCCACU 25 GUGGCUGUAAAAUGCUAAAUCAC 82Table 3Chemical properties of compoundsCompound5'-LModified strands (5'-3')3'-LRef ID NO:SEQ ID NO: RD3693 vA*fG*mA.fU.mG.fA.mU.fU.mU.fA.mG.fC.mA.fU.mU.fU.mU.fA.mC.fA.mG*mC*mC IA1141 11 FIII mG*mC.mU.mG.mU.mA.mA.fA.mA.fU.fG.fC.fU.mA.mA.mA.mU.mC.mA.mU.mC*mU*dQ IS1446 45 RD3694 vU*fC*mC.fU.mA.fU.mA.fA.mG.fA.mC.fU.mU.fA.mA.fA.mC.fC.mC.fA.mG*mA*mC IA1142 12 FIII mU*mC.mU.mG.mG.mG.mU.fU.mU.fA.fA.fG.fU.mC.mU.mU.mA.mU.mA.mG.mG*mA*dQ IS1447 46 RD3695 vA*fU*mC.fC.mU.fU.mA.fA.mA.fU.mC.fG.mG.fU.mA.fU.mA.fA.mG.fC.mU*mG*mG IA1143 13 FIII mC*mA.mG.mC.mU.mU.mA.fU.mA.fC.fC.fG.fA.mU.mU.mU.mA.mA.mG.mG.mA*mU*dQ IS1448 47 RD3696 vU*fA*mA.fG.mC.fA.mA.fG.mC.fA.mU.fU.mC.fA.mA.fC.mC.fA.mU.fG.mA*mU*mG IA1144 14 FIII mA*mU.mC.mA.mU.mG.mG.fU.mU.fG.fA.fA.fU.mG.mC.mU.mU.mG.mC.mU.mU*mA*dQ IS1449 48 RD3697 vU*fG*mC.fU.mU.fU.mU.fC.mG.fU.mA.fC.mA.fU.mC.fU.mU.fG.mU.fU.mC*mA*mC IA1145 15 FIII mU*mG.mA.mA.mC.mA.mA.fG.mA.fU.fG.fU.fA.mC.mG.mA.mA.mA.mA.mG.mC*mA*dQ IS1450 49 RD3698 vU*fA*mU.fC.mU.fG.mA.fU.mA.fU.mC.fU.mG.fA.mU.fC.mA.fC.mC.fA.mU*mU*mC IA1146 16 FIII mA*mA.mU.mG.mG.mU.mG.fA.mU.fC.fA.fG.fA.mU.mA.mU.mC.mA.mG.mA.mU*mA*dQ IS1451 50 RD3699 vU*fU*mC.fA.mU.fC.mU.fG.mA.fU.mA.fU.mC.fU.mG.fA.mU.fC.mA.fC.mC*mA*mU IA1147 17 FIII mU*mG.mG.mU.mG.mA.mU.fC.mA.fG.fA.fU.fA.mU.mC.mA.mG.mA.mU.mG.mA*mA*dQ IS1452 51 RD3700 vA*fU*mC.fU.mC.fU.mU.fA.mG.fU.mU.fC.mA.fU.mU.fU.mG.fC.mU.fG.mA*mA*mA IA1148 18 FIII mU*mU.mC.mA.mG.mC.mA.fA.mA.fU.fG.fA.fA.mC.mU.mA.mA.mG.mA.mG.mA*mU*dQ IS1453 52 RD3701 vA*fA*mU.fA.mU.fC.mU.fC.mU.fU.mA.fG.mU.fU.mC.fA.mU.fU.mU.fG.mC*mU*mG IA1149 19 FIII mA*mG.mC.mA.mA.mA.mU.fG.mA.fA.fC.fU.fA.mA.mG.mA.mG.mA.mU.mA.mU*mU*dQ IS1454 53 RD3702 vU*fA*mG.fC.mU.fG.mU.fU.mG.fU.mG.fG.mA.fA.mA.fG.mC.fU.mC.fG.mU*mG*mA IA1150 20 FIII mC*mA.mC.mG.mA.mG.mC.fU.mU.fU.fC.fC.fA.mC.mA.mA.mC.mA.mG.mC.mU*mA*dQ IS1455 54 RD3703 vU*fU*mG.fU.mG.fC.mA.fA.mG.fU.mC.fC.mA.fA.mA.fU.mG.fU.mG.fU.mC*mA*mA IA1151 twenty one FIII mU*mG.mA.mC.mA.mC.mA.fU.mU.fU.fG.fG.fA.mC.mU.mU.mG.mC.mA.mC.mA*mA*dQ IS1456 55 RD3704 vA*fU*mA.fG.mA.fC.mA.fG.mC.fA.mA.fG.mG.fU.mA.fC.mA.fA.mU.fG.mC*mU*mC IA1152 twenty two FIII mA*mG.mC.mA.mU.mU.mG.fU.mA.fC.fC.fU.fU.mG.mC.mU.mG.mU.mC.mU.mA*mU*dQ IS1457 56 RD3705 vU*fC*mU.fA.mA.fG.mA.fC.mU.fU.mC.fA.mG.fA.mU.fC.mC.fU.mA.fC.mC*mA*mG IA1153 twenty three FIII mU*mG.mG.mU.mA.mG.mG.fA.mU.fC.fU.fG.fA.mA.mG.mU.mC.mU.mU.mA.mG*mA*dQ IS1458 57 RD3706 vU*fC*mA.fA.mA.fC.mA.fC.mA.fU.mC.fA.mA.fU.mG.fG.mA.fG.mU.fA.mC*mU*mG IA1154 twenty four FIII mA*mG.mU.mA.mC.mU.mC.fC.mA.fU.fU.fG.fA.mU.mG.mU.mG.mU.mU.mU.mG*mA*dQ IS1459 58 RD4067 vU*fG*mA.fU.mU.fU.mA.fG.mC.fA.mU.fU.mU.fU.mA.fC.mA.fG.mC.fC.mA*mC*mU IA1269 25 FIII mG*mU.mG.mG.mC.mU.mG.fU.mA.fA.fA.fA.fU.mG.mC.mU.mA.mA.mA.mU.mC*mA*dQ IS1568 59 RD4068 vU*fA*mU.fG.mA.fU.mU.fU.mA.fG.mC.fA.mU.fU.mU.fU.mA.fC.mA.fG.mC*mC*mA IA1270 26 FIII mG*mG.mC.mU.mG.mU.mA.fA.mA.fA.fU.fG.fC.mU.mA.mA.mA.mU.mC.mA.mU*mA*dQ IS1569 60 RD4069 vA*fU*mC.fC.mU.fA.mU.fA.mA.fG.mA.fC.mU.fU.mA.fA.mA.fC.mC.fC.mA*mG*mA IA1271 27 FIII mC*mU.mG.mG.mG.mU.mU.fU.mA.fA.fG.fU.fC.mU.mU.mA.mU.mA.mG.mG.mA*mU*dQ IS1570 61 RD4070 vA*fU*mA.fG.mA.fA.mG.fC.mA.fA.mG.fC.mA.fU.mU.fC.mA.fA.mC.fC.mA*mU*mG IA1272 28 FIII mA*mU.mG.mG.mU.mU.mG.fA.mA.fU.fG.fC.fU.mU.mG.mC.mU.mU.mC.mU.mA*mU*dQ IS1571 62 RD4071 vA*fA*mU.fA.mG.fA.mA.fG.mC.fA.mA.fG.mC.fA.mU.fU.mC.fA.mA.fC.mC*mA*mU IA1273 29 FIII mU*mG.mG.mU.mU.mG.mA.fA.mU.fG.fC.fU.fU.mG.mC.mU.mU.mC.mU.mA.mU*mU*dQ IS1572 63 RD4072 vU*fU*mU.fU.mU.fC.mA.fU.mC.fU.mG.fA.mU.fA.mU.fC.mU.fG.mA.fU.mC*mA*mC IA1274 30 FIII mU*mG.mA.mU.mC.mA.mG.fA.mU.fA.fU.fC.fA.mG.mA.mU.mG.mA.mA.mA.mA*mA*dQ IS1573 64 RD4073 vU*fA*mU.fU.mG.fA.mA.fG.mU.fU.mU.fU.mG.fA.mU.fG.mA.fC.mC.fU.mG*mA*mG IA1275 31 FIII mU*mC.mA.mG.mG.mU.mC.fA.mU.fC.fA.fA.fA.mA.mC.mU.mU.mC.mA.mA.mU*mA*dQ IS1574 65 RD4074 vU*fC*mU.fC.mU.fU.mA.fG.mU.fU.mC.fA.mU.fU.mU.fG.mC.fU.mG.fA.mA*mA*mG IA1276 32 FIII mU*mU.mU.mC.mA.mG.mC.fA.mA.fA.fU.fG.fA.mA.mC.mU.mA.mA.mG.mA.mG*mA*dQ IS1575 66 RD4075 vU*fG*mU.fU.mG.fU.mG.fG.mA.fA.mA.fG.mC.fU.mC.fG.mU.fG.mA.fG.mU*mG*mC IA1277 33 FIII mC*mA.mC.mU.mC.mA.mC.fG.mA.fG.fC.fU.fU.mU.mC.mC.mA.mC.mA.mA.mC*mA*dQ IS1576 67 RD4076 vA*fG*mC.fU.mG.fU.mU.fG.mU.fG.mG.fA.mA.fA.mG.fC.mU.fC.mG.fU.mG*mA*mG IA1278 34 FIII mU*mC.mA.mC.mG.mA.mG.fC.mU.fU.fU.fC.fC.mA.mC.mA.mA.mC.mA.mG.mC*mU*dQ IS1577 68 RD4077 vA*fU*mA.fG.mC.fU.mG.fU.mU.fG.mU.fG.mG.fA.mA.fA.mG.fC.mU.fC.mG*mU*mG IA1279 35 FIII mA*mC.mG.mA.mG.mC.mU.fU.mU.fC.fC.fA.fC.mA.mA.mC.mA.mG.mC.mU.mA*mU*dQ IS1578 69 RD4078 vA*fG*mA.fU.mG.fU.mC.fA.mG.fA.mU.fU.mU.fU.mC.fA.mA.fG.mA.fC.mA*mG*mC IA1280 36 FIII mC*mU.mG.mU.mC.mU.mU.fG.mA.fA.fA.fA.fU.mC.mU.mG.mA.mC.mA.mU.mC*mU*dQ IS1579 70 RD4079 vU*fA*mC.fA.mG.fC.mA.fA.mG.fG.mU.fA.mC.fA.mA.fU.mG.fC.mU.fC.mG*mC*mU IA1281 37 FIII mG*mC.mG.mA.mG.mC.mA.fU.mU.fG.fU.fA.fC.mC.mU.mU.mG.mC.mU.mG.mU*mA*dQ IS1580 71 RD4080 vU*fA*mG.fA.mC.fA.mG.fC.mA.fA.mG.fG.mU.fA.mC.fA.mA.fU.mG.fC.mU*mC*mG IA1282 38 FIII mG*mA.mG.mC.mA.mU.mU.fG.mU.fA.fC.fC.fU.mU.mG.mC.mU.mG.mU.mC.mU*mA*dQ IS1581 72 RD4081 vU*fA*mC.fA.mA.fA.mG.fU.mG.fG.mU.fA.mA.fU.mC.fU.mC.fG.mU.fA.mU*mG*mG IA1283 39 FIII mC*mA.mU.mA.mC.mG.mA.fG.mA.fU.fU.fA.fC.mC.mA.mC.mU.mU.mU.mG.mU*mA*dQ IS1582 73 RD4082 vU*fU*mC.fG.mU.fU.mC.fU.mC.fU.mC.fC.mC.fU.mG.fA.mA.fA.mG.fC.mA*mU*mG IA1284 40 FIII mA*mU.mG.mC.mU.mU.mU.fC.mA.fG.fG.fG.fA.mG.mA.mG.mA.mA.mC.mG.mA*mA*dQ IS1583 74 RD4083 vA*fA*mA.fC.mU.fC.mU.fG.mG.fA.mG.fC.mU.fU.mG.fU.mU.fC.mA.fA.mG*mU*mU IA1285 41 FIII mA*mC.mU.mU.mG.mA.mA.fC.mA.fA.fG.fC.fU.mC.mC.mA.mG.mA.mG.mU.mU*mU*dQ IS1584 75 RD4084 vU*fA*mU.fU.mC.fU.mA.fC.mA.fG.mC.fA.mG.fU.mA.fC.mU.fG.mA.fG.mC*mA*mA IA1286 42 FIII mU*mG.mC.mU.mC.mA.mG.fU.mA.fC.fU.fG.fC.mU.mG.mU.mA.mG.mA.mA.mU*mA*dQ IS1585 76 RD4085 vU*fU*mC.fA.mG.fG.mU.fG.mC.fA.mC.fG.mA.fA.mA.fC.mC.fC.mU.fG.mG*mU*mG IA1287 43 FIII mA*mC.mC.mA.mG.mG.mG.fU.mU.fU.fC.fG.fU.mG.mC.mA.mC.mC.mU.mG.mA*mA*dQ IS1586 77 RD4086 vU*fC*mA.fA.mC.fA.mA.fU.mU.fA.mC.fG.mU.fU.mU.fU.mU.fA.mG.fG.mU*mG*mA IA1288 44 FIII mC*mA.mC.mC.mU.mA.mA.fA.mA.fA.fC.fG.fU.mA.mA.mU.mU.mG.mU.mU.mG*mA*dQ IS1587 78 RD4113 eA*fG*mA.fU.mG.fA.mU.fU.mU.fA.mG.fC.mA.fU.mU.fU.mU.fA.mC.fA.mG*mC*mC IA1267 11 FXX mG*mC.mU.mG.mU.mA.mA.fA.mA.fU.fG.fC.fU.mA.mA.mA.mU.mC.mA.mU.mC*mU*dQ IS1446 45 RD4116 eA*fU*mC.fC.mU.fU.mA.fA.mA.fU.mC.fG.mG.fU.mA.fU.mA.fA.mG.fC.mU*mG*mG IA1265 13 FXX mC*mA.mG.mC.mU.mU.mA.fU.mA.fC.fC.fG.fA.mU.mU.mU.mA.mA.mG.mG.mA*mU*dQ IS1448 47 RD4134 eA*fG*mA.fU.mG.fA.mU.fU.mU.fA.mG.fC.mA.fU.mU.fU.mU.fA.mC.fA.mG*mC*mC IA1267 11 FIII mG*mC.mU.mG.mU.mA.mA.fA.mA.fU.fG.fC.fU.mA.mA.mA.mU.mC.mA.mU.mC*mU*dQ IS1446 45 RD4135 eA*fU*mC.fC.mU.fU.mA.fA.mA.fU.mC.fG.mG.fU.mA.fU.mA.fA.mG.fC.mU*mG*mG IA1265 13 FIII mC*mA.mG.mC.mU.mU.mA.fU.mA.fC.fC.fG.fA.mU.mU.mU.mA.mA.mG.mG.mA*mU*dQ IS1448 47 RD4270 eU*fG*mU.fU.mG.fU.mG.fG.mA.fA.mA.fG.mC.fU.mC.fG.mU.fG.mA.fG.mU*mG*mC IA1306 33 FIII mC*mA.mC.mU.mC.mA.mC.fG.mA.fG.fC.fU.fU.mU.mC.mC.mA.mC.mA.mA.mC*mA*dQ IS1576 67 RD4271 eU*fG*mU.fU.mG.fU.mG.fG.mA.fA.mA.fG.mC.fU.mC.fG.mU.fG.mA.fG.mU*mG*mC IA1306 33 FX *mC*mA.mC.mU.mC.mA.mC.fG.mA.fG.fC.fU.fU.mU.mC.mC.mA.mC.mA.mA.mC*mA*dQ IS1576 67 RD4275 eA*fG*mA.fU.mG.fA.mU.fU.mU.fA.mG.fC.mA.fU.mU.fU.mU.fA.mC.fA.mG*mC*mC IA1267 11 FIII mG*mC.mU.mG.mU.mA.mA.fA.mA.fU.fG.fC.fU.mA.mA.mA.mU.mC.mA.mU.mC*mU FIV IS1566 79 RD4277 eA*fU*mC.fC.mU.fU.mA.fA.mA.fU.mC.fG.mG.fU.mA.fU.mA.fA.mG.fC.mU*mG*mG IA1265 13 FIII mC*mA.mG.mC.mU.mU.mA.fU.mA.fC.fC.fG.fA.mU.mU.mU.mA.mA.mG.mG.mA*mU FIV IS1565 80 RD4279 eU*fG*mU.fU.mG.fU.mG.fG.mA.fA.mA.fG.mC.fU.mC.fG.mU.fG.mA.fG.mU*mG*mC IA1306 33 FIII mC*mA.mC.mU.mC.mA.mC.fG.mA.fG.fC.fU.fU.mU.mC.mC.mA.mC.mA.mA.mC*mA FIV IS1620 81 RD4416 eU*fG*mA.fU.mU.fU.mA.fG.mC.fA.mU.fU.mU.fU.mA.fC.mA.fG.mC.fC.mA*mC*mU IA1315 25 FIII mG*mU.mG.mG.mC.mU.mG.fU.mA.fA.fA.fA.fU.mG.mC.mU.mA.mA.mA.mU.mC.mA*dQ FIV IS1644 82 RD4314 eA*fA*mU.fU.mA.fC.mC.fU.mA.fA.mU.fG.mU.fA.mA.fG.mC.fC.mU.fA.mU*mG*mG IA1307 83 FVI mC*mA.mU.mA.mG.mG.mC.fU.mU.fA.fC.fA.fU.mU.mA.mG.mG.mU.mA.mA.mU*mU*dQ IS1621 90 RD4315 eU*fA*mU.fA.mC.fA.mU.fC.mU.fG.mC.fA.mG.fU.mG.fU.mG.fU.mG.fA.mA*mG*mC IA1308 84 FVI mC*mU.mU.mC.mA.mC.mA.fC.mA.fC.fU.fG.fC.mA.mG.mA.mU.mG.mU.mA.mU*mA*dQ IS1622 91 RD4316 eA*fG*mC.fA.mA.fG.mC.fU.mG.fA.mU.fG.mA.fU.mC.fU.mG.fG.mC.fU.mG*mU*mC IA1309 85 FVI mA*mC.mA.mG.mC.mC.mA.fG.mA.fU.fC.fA.fU.mC.mA.mG.mC.mU.mU.mG.mC*mU*dQ IS1623 92 RD4317 eA*fG*mU.fU.mU.fU.mG.fA.mU.fG.mA.fC.mC.fU.mG.fA.mG.fU.mG.fA.mA*mU*mC IA1310 86 FVI mA*mU.mU.mC.mA.mC.mU.fC.mA.fG.fG.fU.fC.mA.mU.mC.mA.mA.mA.mA.mC*mU*dQ IS1624 93 RD4318 eU*fA*mG.fA.mA.fG.mC.fC.mA.fG.mA.fG.mA.fA.mG.fA.mA.fA.mU.fG.mC*mU*mG IA1311 87 FVI mA*mG.mC.mA.mU.mU.mU.fC.mU.fU.fC.fU.fC.mU.mG.mG.mC.mU.mU.mC.mU*mA*dQ IS1625 94 RD4319 eU*fA*mA.fG.mA.fG.mC.fC.mA.fA.mG.fG.mC.fU.mU.fC.mA.fU.mG.fG.mC*mA*mU IA1312 88 FVI mU*mG.mC.mC.mA.mU.mG.fA.mA.fG.fC.fC.fU.mU.mG.mG.mC.mU.mC.mU.mU*mA*dQ IS1626 95 RD4320 eU*fA*mA.fA.mG.fA.mC.fC.mU.fG.mG.fG.mC.fA.mG.fA.mA.fG.mU.fA.mG*mG*mC IA1313 89 FVI mC*mC.mU.mA.mC.mU.mU.fC.mU.fG.fC.fC.fC.mA.mG.mG.mU.mC.mU.mU.mU*mA*dQ IS1627 96 RD4335 eU*fG*mA.fU.mU.fU.mA.fG.mC.fA.mU.fU.mU.fU.mA.fC.mA.fG.mC.fC.mA*mC*mU IA1315 25 FVI mG*mU.mG.mG.mC.mU.mG.fUëmA.fA.fA.fA.fU.mG.mC.mU.mA.mA.mA.mU.mC.mA*dQ*t6.mC IS1629 82 RD4362 eU*fG*mA.fU.mU.fU.mA.fG.mC.fA.mU.fU.mU.fU.mA.fC.mA.fG.mC.fC.mA*mC*mU IA1315 25 FVI mG*mU.mG.mG.mC.mU.mG.fUëmA.fA.fA.fA.fU.mG.mC.mU.mA.mA.mA.mU.mC.mA*dQ FVII IS1629 82Example 1: Effects of modified oligonucleotides targeting human LRRK2 in hLRRK2 transgenic mice

在活體內hLRRK2基因轉殖小鼠PD研究中評估化合物。動物在第1天經由腦室內注射接受單一媒劑或0.2 μg (10 mg/kg)劑量(n=3隻/組)。每天觀察動物之行為變化。在第15天及第29天收集腦區域，且將組織立即置於均質管中，快速冷凍，接著保持在-80℃以用於基因表現分析。Compounds were evaluated in an in vivo hLRRK2 transgenic mouse PD study. Animals received a single vehicle or 0.2 μg (10 mg/kg) dose by intracerebroventricular injection on day 1 (n=3/group). Animals were observed daily for behavioral changes. Brain regions were collected on days 15 and 29, and tissues were immediately placed in homogenizer tubes, snap frozen, and then kept at -80°C for gene expression analysis.

根據RNeasy Micro套組(Qiagen目錄號74004)說明書實施RNA分離。RNA分離後，將96孔板置於冰上，同時準備qRT-PCR反應。向MicroAmp光學96孔板(0.2 mL)中之含有5 μl TaqMan快速病毒1步混合母液(Thermo Fisher編號44444432)、1 μl LRRK2 TaqMan基因表現分析(Thermo Fisher：Hs01115057_m1)、1 μl GAPDH (VIC) TaqMan基因表現分析(Thermo Fisher：Mm99999915_g1, VIC)及11 μl RT-PCR級無核酸酶水之反應混合物中添加2 μl RNA。使用QuantStudio3 qPCR機，利用以下循環實施qPCR：50℃持續1分鐘，95℃持續20秒，且以95℃持續15秒及60℃持續1分鐘進行40個循環。RNA isolation was performed according to the instructions of the RNeasy Micro Kit (Qiagen catalog number 74004). After RNA isolation, the 96-well plate was placed on ice while preparing the qRT-PCR reaction. 2 μl of RNA was added to a reaction mixture containing 5 μl of TaqMan Fast Virus 1-Step Master Mix (Thermo Fisher catalog number 44444432), 1 μl of LRRK2 TaqMan Gene Expression Assay (Thermo Fisher: Hs01115057_m1), 1 μl of GAPDH (VIC) TaqMan Gene Expression Assay (Thermo Fisher: Mm99999915_g1, VIC), and 11 μl of RT-PCR grade nuclease-free water in a MicroAmp Optical 96-well plate (0.2 mL). qPCR was performed using a QuantStudio3 qPCR machine using the following cycles: 50°C for 1 min, 95°C for 20 sec, and 40 cycles of 95°C for 15 sec and 60°C for 1 min.

結果在下表中呈現為相對於媒劑對照之LRRK2抑制百分比。表4平均LRRK2抑制研究編號化合物D15STRD15MBD15CTXD15CERVD15HPCD15BSD15CBMD15THORD15THOR10號RD4086213182110號RD408510210號RD408413241610號RD407641161511號RD43145760526511號RD42753554265611號RD43161328132611號RD4317192282312號RD43194032202512號RD43154528271812號RD4277192512812號RD43183624182513號RD43618576831559676913號RD436241535071337049776613號RD43354036029593616414號RD42792618291414號RD42702217401914號RD4271351748402號RD36953841577753412號RD36961938555431362號RD3693142554343341612號RD36977284034312號RD36944322226173號RD3701253893232286543號RD370030361931264810413號RD369834303123505143號RD37021428017132630573號RD36992571026231918504號RD370361654號RD370664184號RD37051063664號RD3704012535號RD411347555號RD41343439515號RD40691120506號RD413553239406號RD40756331336號RD411632977號RD4067705960787號RD4068484539597號RD4077131216147號RD407034818267號RD407819210478號RD4082362010228號RD408317150208號RD4080978號RD4079448號RD40814116109號RD4073685144559號RD4071594337469號RD4074593534389號RD407244251720研究編號化合物D29STRD29MBD29CTXD29CERVD29HPCD29CBMD29THORD29THOR2號RD36953117154329302號RD3696253254014112號RD369336404652256349522號RD36973120152784632372號RD3694296393626203號RD37013746604645143號RD3700131642425153號RD369823230673號RD3702283462034233號RD369933643333244號RD3703507253515184號RD37062218312562352604號RD370534352419481924274號RD37044212143242513CTX皮質HPC海馬體STR紋狀體CBM小腦BS腦幹CERV頸脊髓THOR胸脊髓LUMB腰脊髓MB中腦D15第15天D29第29天SEQ ID NO: 1等效內容及範圍The results are presented in the table below as percent inhibition of LRRK2 relative to vehicle control.Table 4Average LRRK2 inhibitionStudy No.CompoundD15STRD15MBD15CTXD15CERVD15HPCD15BSD15CBMD15THORD15THOR No. 10 RD4086 2 13 18 twenty one No. 10 RD4085 10 2 No. 10 RD4084 13 2 4 16 No. 10 RD4076 4 1 16 15 No. 11 RD4314 57 60 52 65 No. 11 RD4275 35 54 26 56 No. 11 RD4316 13 28 13 26 No. 11 RD4317 19 twenty two 8 twenty three No. 12 RD4319 40 32 20 25 No. 12 RD4315 45 28 27 18 No. 12 RD4277 19 25 1 28 No. 12 RD4318 36 twenty four 18 25 No. 13 RD4361 8 57 68 31 55 9 67 69 No. 13 RD4362 41 53 50 71 33 70 49 77 66 No. 13 RD4335 40 3 60 29 59 3 61 64 No. 14 RD4279 26 18 29 14 No. 14 RD4270 twenty two 17 40 19 No. 14 RD4271 35 17 48 40 No. 2 RD3695 38 41 57 77 53 41 No. 2 RD3696 19 38 55 54 31 36 No. 2 RD3693 14 25 54 34 33 41 61 No. 2 RD3697 7 28 40 34 31 No. 2 RD3694 4 32 twenty two 26 17 No. 3 RD3701 25 38 9 32 32 28 6 54 No. 3 RD3700 30 36 19 31 26 48 10 41 No. 3 RD3698 34 30 3 12 3 50 5 14 No. 3 RD3702 14 28 0 17 13 26 30 57 No. 3 RD3699 25 7 10 26 twenty three 19 18 50 No. 4 RD3703 6 16 5 No. 4 RD3706 6 4 18 No. 4 RD3705 10 6 36 6 No. 4 RD3704 0 12 53 No. 5 RD4113 47 55 No. 5 RD4134 34 39 51 No. 5 RD4069 11 20 50 No. 6 RD4135 53 2 39 40 No. 6 RD4075 63 31 33 No. 6 RD4116 32 9 7 No. 7 RD4067 70 59 60 78 No. 7 RD4068 48 45 39 59 No. 7 RD4077 13 12 16 14 No. 7 RD4070 34 8 18 26 No. 7 RD4078 19 2 10 47 No. 8 RD4082 36 20 10 twenty two No. 8 RD4083 17 15 0 20 No. 8 RD4080 9 7 No. 8 RD4079 4 4 No. 8 RD4081 4 1 16 10 No. 9 RD4073 68 51 44 55 No. 9 RD4071 59 43 37 46 No. 9 RD4074 59 35 34 38 No. 9 RD4072 44 25 17 20Study No.CompoundD29STRD29MBD29CTXD29CERVD29HPCD29CBMD29THORD29THOR No. 2 RD3695 31 17 15 43 29 30 No. 2 RD3696 25 3 25 40 14 11 No. 2 RD3693 36 40 46 52 25 63 49 52 No. 2 RD3697 31 20 15 27 8 46 32 37 No. 2 RD3694 29 6 39 36 26 20 No. 3 RD3701 37 46 60 46 45 14 No. 3 RD3700 13 16 4 twenty four 25 15 No. 3 RD3698 twenty three twenty three 0 6 7 No. 3 RD3702 28 34 6 20 34 twenty three No. 3 RD3699 33 64 33 33 twenty four No. 4 RD3703 5 0 7 25 35 15 18 No. 4 RD3706 twenty two 18 31 25 62 35 26 0 No. 4 RD3705 34 35 twenty four 19 48 19 twenty four 27 No. 4 RD3704 42 1 twenty one 43 twenty four 25 13CTX LeatherHPC HippocampusSTR TextureCBM CerebellumBS Brain stemCERV Cervical spinal cordTHOR Thoracic spinal cordLUMB Lumbar spinal cordMB MidbrainD15 Day 15D29 Day 29SEQ ID NO: 1Equivalent content and scope

應理解，本揭示案不限於本文明確闡述之任何或所有特定實施例，且因此當然可有所變化。亦應理解，本文所用之術語僅係出於描述特定實施例之目的，而不意欲具有限制性。It should be understood that the present disclosure is not limited to any or all of the specific embodiments explicitly described herein, and therefore may of course vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting.

除非另有定義，否則本文所用之所有技術及科學術語均具有與熟習本揭示案所屬領域技術者所通常理解相同之含義。儘管與本文所闡述之任何方法及材料類似或等同者亦可用於實踐或測試本揭示案，但現闡述較佳方法及材料。如熟習此項技術者將易於明瞭，且根據本文所用術語應理解，在本文中定義詞語或術語之情形下，該等詞語或術語之適用性不應限於緊接在定義之前或之後的實施例，而是應在語境允許之情形下在整個本揭示案中使用。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used to practice or test this disclosure, the preferred methods and materials are now described. As will be readily apparent to those skilled in the art and understood from the terms used herein, where a word or term is defined herein, the applicability of such word or term should not be limited to the embodiments immediately preceding or following the definition, but should be used throughout this disclosure as the context permits.

本說明書中所引用之所有出版物及專利經引用以揭示並闡述與所引用出版物相關之方法及/或材料。所有此等出版物及專利均係以引用方式併入本文中，如同每一個別出版物或專利明確且個別地指示以引用方式併入一般。此種以引用方式併入明確地限於所引用出版物及專利中所闡述之方法及/或材料，且不延伸至來自所引用出版物及專利之任何詞典式定義(亦即，所引用出版物及專利中的在本揭示案中未再明確重複之任何詞典式定義不應視為如此，且不應解讀為定義隨附申請專利範圍中出現之任何術語)。若任何併入之參考文獻與本揭示案之間存在衝突，則應以本揭示案為準。另外，本揭示案中屬於先前技術內之任何特定實施例可明確地自任一或多項技術方案中排除。由於認為此等實施例為熟習此項技術者所已知，故可將其排除，即使本文中未明確陳述該排除。出於任何原因，無論是否與先前技術之存在相關，本揭示案之任何特定實施例均可自任何技術方案中排除。All publications and patents cited in this specification are cited to disclose and describe methods and/or materials related to the cited publications. All such publications and patents are incorporated herein by reference as if each individual publication or patent was expressly and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and/or materials described in the cited publications and patents and does not extend to any dictionary definitions from the cited publications and patents (that is, any dictionary definitions in the cited publications and patents that are not expressly repeated in this disclosure should not be regarded as such and should not be interpreted as defining any term appearing in the scope of the attached patent applications). In the event of a conflict between any incorporated reference and the present disclosure, the present disclosure shall control. In addition, any specific embodiment of the present disclosure that is within the prior art may be explicitly excluded from any one or more technical solutions. Such embodiments may be excluded because they are considered to be known to those skilled in the art, even if the exclusion is not explicitly stated herein. Any specific embodiment of the present disclosure may be excluded from any technical solution for any reason, whether or not it is related to the existence of the prior art.

對任何出版物之引用係由於其揭示內容早於申請日，而不應解釋為承認本揭示案無權因先前揭示內容而早於此出版物。此外，所提供之公開日期可能與實際公開日期不同，可能需要獨立確認。The citation of any publication for its disclosure prior to the filing date should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Furthermore, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

如熟習此項技術者在閱讀本揭示案後將明瞭，本文所闡述及闡釋之個別實施例中之每一者具有分立之組件及特徵，該等組件及特徵可在不背離本揭示案之範圍或精神之情形下容易地與其他若干實施例中之任一者之特徵分離或組合。任何所列舉之方法可按所列舉事件之順序或按在邏輯上可能之任何其他順序來實施。As will be apparent to those skilled in the art after reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be easily separated or combined with the features of any of the other several embodiments without departing from the scope or spirit of this disclosure. Any recited method may be implemented in the order of the recited events or in any other order that is logically possible.

在申請專利範圍中，除非指示相反情形或自上下文中另外明顯可見，否則諸如「一種/個(a、an)」及「該(the)」等冠詞可意指一種/個或一種/個以上。除非上下文另有明確指示或要求，否則無論性別代詞(例如男性、女性、無性、其他等)在本文中何處使用，該代詞均應解釋為性別中性的(例如，解釋為同等地指所有性別)，而不考慮隱含性別。除非上下文另有明確指示或要求，否則無論在本文中何處使用，單數形式使用之詞語包括複數，且複數形式使用之詞語包括單數。除非指示相反情形或自上下文中另外明顯可見，否則若一個、一個以上或所有群組成員存在於、用於給定產物或製程或以其他方式與給定產物或製程相關，則在群組之一或多個成員之間包括「或」之技術方案或描述視為滿足條件的。本揭示案包括其中恰好一個群組成員存在於、用於給定產物或製程或以其他方式與給定產物或製程相關之實施例。本揭示案包括其中一個以上或所有群組成員存在於、用於給定產物或製程或以其他方式與給定產物或製程相關之實施例。In the claims, unless otherwise indicated or otherwise clear from the context, articles such as "a," "an," and "the" may mean one or more than one. Unless the context clearly indicates or requires otherwise, wherever a gender pronoun (e.g., masculine, feminine, asexual, other, etc.) is used herein, the pronoun should be construed as gender neutral (e.g., construed as referring equally to all genders) without regard to implied gender. Unless the context clearly indicates or requires otherwise, wherever used herein, words used in the singular include the plural, and words used in the plural include the singular. Unless indicated to the contrary or otherwise apparent from the context, a technical solution or description including an "or" between one or more members of a group is deemed to satisfy the condition if one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or process. The present disclosure includes embodiments in which exactly one of the group members is present in, used in, or otherwise related to a given product or process. The present disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or process.

此外，本揭示案涵蓋將來自所列示技術方案中之一或多者之一或多種限制、要素、條款及說明性術語引入至另一技術方案中之所有變化形式、組合及排列。舉例而言，附屬於另一技術方案之任一技術方案可經修改以包括在附屬於同一基礎技術方案之任何其他技術方案中找到之一或多種限制。倘若以列表形式(例如，以馬庫什群組(Markush group)格式)呈現要素，則亦揭示該等要素之每一亞組，且可自該群組移除任何要素。應理解，一般而言，倘若稱本揭示案或本揭示案之態樣包含特定要素及/或特徵，則本揭示案之某些實施例或本揭示案之態樣係由此等要素及/或特徵組成，或基本上由其組成。出於簡潔性目的，在本文中不以同樣的語言明確陳述彼等實施例。亦應注意，術語「包含」及「含有」意欲為開放性的且允許包括其他要素或步驟。在給出範圍之情形下，除非另有指定，否則端點包括在此等範圍中。此外，除非另有指示或自上下文及熟習此項技術者之理解另外明顯可見，否則表述為範圍之值可在本揭示案之不同實施例中假設所陳述範圍內之任一具體值或子範圍，直至該範圍之下限單位之十分之一，除非上下文另外明確指示。In addition, this disclosure covers all variations, combinations and arrangements of one or more restrictions, elements, clauses and explanatory terms from one or more of the listed technical solutions introduced into another technical solution. For example, any technical solution attached to another technical solution can be modified to include one or more restrictions found in any other technical solution attached to the same basic technical solution. If the elements are presented in a list form (for example, in a Markush group format), each subgroup of these elements is also disclosed, and any element can be removed from the group. It should be understood that, in general, if it is said that this disclosure or the aspect of this disclosure includes specific elements and/or features, then some embodiments of this disclosure or the aspect of this disclosure are composed of these elements and/or features, or are basically composed of them. For the purpose of brevity, they are not clearly stated in the same language herein. It should also be noted that the terms "comprising" and "including" are intended to be open ended and allow for the inclusion of other elements or steps. Where ranges are given, the endpoints are included in such ranges unless otherwise specified. In addition, unless otherwise indicated or otherwise apparent from the context and the understanding of one skilled in the art, values expressed as ranges may assume any specific value or sub-range within the stated range in different embodiments of the present disclosure, up to one tenth of the unit of the lower limit of the range, unless the context clearly indicates otherwise.

熟習此項技術者將認識到，或能夠僅使用常規實驗確定本文所闡述具體實施例之許多等效形式。本文所闡述之本發明實施例之範圍不意欲限於以上說明，而是如隨附申請專利範圍中所陳述。熟習此項技術者應瞭解，在不背離如以下申請專利範圍中所定義之本揭示案之精神或範圍之情形下，可對本說明作出各種變化及修改。Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but rather as set forth in the accompanying claims. Those skilled in the art will appreciate that various changes and modifications may be made to the description without departing from the spirit or scope of the disclosure as defined in the following claims.

TW202506137A_113122952_SEQL.xmlTW202506137A_113122952_SEQL.xml

Claims (133)

Translated fromChinese

一種化合物，其包含長度為14至30個連接核苷之經修飾之寡核苷酸，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個鄰接核鹼基之核鹼基序列。A compound comprising a modified oligonucleotide having a length of 14 to 30 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 adjacent nucleobases of any nucleobase sequence of SEQ ID NOs: 11-44 and 83-89.一種化合物，其包含長度為14至23個連接核苷之經修飾之寡核苷酸，該經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之核鹼基序列之核鹼基序列。A compound comprising a modified oligonucleotide of 14 to 23 linked nucleosides in length, the modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89.一種化合物，其包含經修飾之寡核苷酸，該經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89中之任一者組成之群的核鹼基序列。A compound comprising a modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89.如請求項1至3中任一項之化合物，其中該經修飾之寡核苷酸與SEQ ID NO: 1或2至少80%、至少85%、至少90%或至少95%互補。The compound of any one of claims 1 to 3, wherein the modified oligonucleotide is at least 80%, at least 85%, at least 90% or at least 95% complementary to SEQ ID NO: 1 or 2.如請求項1至4中任一項之化合物，其中該經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。The compound of any one of claims 1 to 4, wherein the modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.如請求項1至5中任一項之化合物，其中該化合物為雙股的。The compound of any one of claims 1 to 5, wherein the compound is bistranded.一種化合物，其包含長度為14至23個連接核苷之第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89或45-82及90-96中之任一核鹼基序列之至少14個、至少15個、至少16個、至少17個、至少18個、至少19個、至少20個、至少21個、至少22個、至少23個鄰接核鹼基之核鹼基序列；及長度為14至23個連接核苷之第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有與該第一經修飾之寡核苷酸互補之區域。A compound comprising a first modified oligonucleotide having a length of 14 to 23 linked nucleosides, the first modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 adjacent nucleosides of any one of SEQ ID NOs: 11-44 and 83-89 or 45-82 and 90-96; and a second modified oligonucleotide having a length of 14 to 23 linked nucleosides, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.一種化合物，其包含長度為14至23個連接核苷之第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89或45-82及90-96中之任一者之核鹼基序列之核鹼基序列；及長度為14至23個連接核苷之第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有與該第一經修飾之寡核苷酸互補之區域。A compound comprising a first modified oligonucleotide having a length of 14 to 23 linked nucleosides, the first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of any one of SEQ ID NOs: 11-44 and 83-89 or 45-82 and 90-96; and a second modified oligonucleotide having a length of 14 to 23 linked nucleosides, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.一種化合物，其包含第一經修飾之寡核苷酸，該第一經修飾之寡核苷酸具有選自由SEQ ID NO: 11-44及83-89或45-82及90-96中之任一者組成之群的核鹼基序列；及長度為19至23個連接核苷之第二經修飾之寡核苷酸，該第二經修飾之寡核苷酸具有與該第一經修飾之寡核苷酸互補之區域。A compound comprising a first modified oligonucleotide having a nucleobase sequence selected from the group consisting of any one of SEQ ID NOs: 11-44 and 83-89 or 45-82 and 90-96; and a second modified oligonucleotide having a length of 19 to 23 linked nucleosides, the second modified oligonucleotide having a region complementary to the first modified oligonucleotide.如請求項7至9中任一項之化合物，其中該第一經修飾之寡核苷酸在其長度上與SEQ ID NO: 1或2具有至少80%、至少85%、至少90%或至少95%之互補性或一致性。A compound as in any one of claims 7 to 9, wherein the first modified oligonucleotide has at least 80%, at least 85%, at least 90% or at least 95% complementarity or identity with SEQ ID NO: 1 or 2 in its length.如請求項7至10中任一項之化合物，其中該第一經修飾之寡核苷酸與SEQ ID NO: 1或2中同該第一經修飾之寡核苷酸長度相同之區域具有至少1個、至少2個、至少3個失配。The compound of any one of claims 7 to 10, wherein the first modified oligonucleotide has at least 1, at least 2, at least 3 mismatches with a region of SEQ ID NO: 1 or 2 that is the same length as the first modified oligonucleotide.如請求項7至11中任一項之化合物，其中該第一經修飾之寡核苷酸與該第二經修飾之寡核苷酸之間的該互補區之長度為14至23個連接核苷。The compound of any one of claims 7 to 11, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide has a length of 14 to 23 linked nucleosides.如請求項7至11中任一項之化合物，其中該第一經修飾之寡核苷酸與該第二經修飾之寡核苷酸之間的該互補區之長度為19至23個連接核苷。The compound of any one of claims 7 to 11, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide has a length of 19 to 23 linked nucleosides.如請求項7至11中任一項之化合物，其中該第一經修飾之寡核苷酸與該第二經修飾之寡核苷酸之間的該互補區之長度為21至23個連接核苷。A compound as in any one of claims 7 to 11, wherein the complementary region between the first modified oligonucleotide and the second modified oligonucleotide has a length of 21 to 23 linked nucleosides.如請求項7至11中任一項之化合物，其中該第一經修飾之寡核苷酸與該第二經修飾之寡核苷酸完全互補。A compound as in any one of claims 7 to 11, wherein the first modified oligonucleotide and the second modified oligonucleotide are completely complementary to each other.如請求項7至15中任一項之化合物，其中該第一經修飾之寡核苷酸包含至少一種選自經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基的修飾。The compound of any one of claims 7 to 15, wherein the first modified oligonucleotide comprises at least one modification selected from a modified internucleoside linkage, a modified sugar, and a modified nucleobase.如請求項7至16中任一項之化合物，其中該第二經修飾之寡核苷酸包含至少一種選自由經修飾之核苷間鍵聯、經修飾之糖及經修飾之核鹼基組成之群的修飾。The compound of any one of claims 7 to 16, wherein the second modified oligonucleotide comprises at least one modification selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase.如請求項5、16及17中任一項之化合物，其中該經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或甲基膦酸酯核苷間鍵聯。The compound of any one of claims 5, 16 and 17, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage or a methylphosphonate internucleoside linkage.如請求項18之化合物，其中該硫代磷酸酯核苷間鍵聯或該甲基膦酸酯核苷間鍵聯位於該第一經修飾之寡核苷酸或該第二經修飾之寡核苷酸的3’末端或位於該第一經修飾之寡核苷酸的5’末端。A compound as claimed in claim 18, wherein the phosphorothioate nucleoside linkage or the methylphosphonate nucleoside linkage is located at the 3' end of the first modified oligonucleotide or the second modified oligonucleotide or at the 5' end of the first modified oligonucleotide.如請求項5、16及17中任一項之化合物，其中該經修飾之糖包含選自由鹵素、烷氧基及雙環糖組成之群的修飾。The compound of any one of claims 5, 16 and 17, wherein the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugar.如請求項20之化合物，其中該經修飾之糖包含2’-F修飾。The compound of claim 20, wherein the modified sugar comprises a 2'-F modification.如請求項20之化合物，其中該經修飾之糖包含2’-OMe修飾。The compound of claim 20, wherein the modified sugar comprises a 2'-OMe modification.如請求項7至15中任一項之化合物，其中該第一經修飾之寡核苷酸之每一核苷包含經修飾之糖。The compound of any one of claims 7 to 15, wherein each nucleoside of the first modified oligonucleotide comprises a modified sugar.如請求項7至15中任一項之化合物，其中該第二經修飾之寡核苷酸之每一核苷包含經修飾之糖。The compound of any one of claims 7 to 15, wherein each nucleoside of the second modified oligonucleotide comprises a modified sugar.如請求項23或24之化合物，其中該經修飾之糖包含選自由鹵素、烷氧基及雙環糖或其組合組成之群的修飾。The compound of claim 23 or 24, wherein the modified sugar comprises a modification selected from the group consisting of halogen, alkoxy and bicyclic sugar or a combination thereof.如請求項25之化合物，其中該經修飾之糖包含選自由LNA、cEt、2’-MOE、2’-F、2’-OMe及2’-去氧或其組合組成之群的修飾。The compound of claim 25, wherein the modified sugar comprises a modification selected from the group consisting of LNA, cEt, 2’-MOE, 2’-F, 2’-OMe and 2’-deoxy or a combination thereof.如請求項26之化合物，其中該第一經修飾之寡核苷酸包含不超過十個2’-F糖修飾。A compound as claimed in claim 26, wherein the first modified oligonucleotide comprises no more than ten 2'-F sugar modifications.如請求項27之化合物，其中該第二經修飾之寡核苷酸包含不超過五個2’-F糖修飾。A compound as claimed in claim 27, wherein the second modified oligonucleotide comprises no more than five 2'-F sugar modifications.如任一前述請求項之化合物，其包含結合基團。A compound as claimed in any preceding claim, comprising a binding group.如請求項29之化合物，其中該結合基團連接至該經修飾之寡核苷酸之5’端。A compound as claimed in claim 29, wherein the binding group is linked to the 5' end of the modified oligonucleotide.如請求項29或30之化合物，其中該結合基團包含靶向部分。A compound as claimed in claim 29 or 30, wherein the binding group comprises a targeting moiety.如請求項31之化合物，其中該靶向部分包含一或多種原肌凝蛋白受體B (TrkB)配位體。A compound as claimed in claim 31, wherein the targeting moiety comprises one or more tropomyosin receptor B (TrkB) ligands.如請求項32之化合物，其中該經修飾之寡核苷酸為該第二經修飾之寡核苷酸。The compound of claim 32, wherein the modified oligonucleotide is the second modified oligonucleotide.如請求項33之化合物，其中該一或多種TrkB配位體連接至該經修飾之寡核苷酸之5’端。The compound of claim 33, wherein the one or more TrkB ligands are linked to the 5' end of the modified oligonucleotide.如請求項33之化合物，其中該一或多種TrkB配位體連接至該經修飾之寡核苷酸之3’端。The compound of claim 33, wherein the one or more TrkB ligands are linked to the 3' end of the modified oligonucleotide.如請求項33之化合物，其中該一或多種TrkB配位體連接至該經修飾之寡核苷酸之5’端及3’端。The compound of claim 33, wherein the one or more TrkB ligands are linked to the 5' end and the 3' end of the modified oligonucleotide.如請求項33之化合物，其中該一或多種TrkB配位體係選自式I-式XX中之任一者。The compound of claim 33, wherein the one or more TrkB ligands are selected from any one of Formula I to Formula XX.如請求項29至37中任一項之化合物，其中該結合基團包含一或多種脂質。A compound as in any one of claims 29 to 37, wherein the binding group comprises one or more lipids.如請求項38之化合物，其中該經修飾之寡核苷酸為該第二經修飾之寡核苷酸。The compound of claim 38, wherein the modified oligonucleotide is the second modified oligonucleotide.如請求項38或39之化合物，其中該一或多種脂質連接至該經修飾之寡核苷酸之核苷間鍵聯。The compound of claim 38 or 39, wherein the one or more lipids are linked to the internucleoside linkage of the modified oligonucleotide.如請求項38至40中任一項之化合物，其中該經修飾之寡核苷酸之該核苷間鍵聯係選自式XXI-式XXIV中之任一者。The compound of any one of claims 38 to 40, wherein the internucleoside linkage of the modified oligonucleotide is selected from any one of Formula XXI to Formula XXIV.如請求項32至41中任一項之化合物，其中該經修飾之寡核苷酸包含一或多種TrkB配位體及一或多種脂質。The compound of any one of claims 32 to 41, wherein the modified oligonucleotide comprises one or more TrkB ligands and one or more lipids.如請求項42之化合物，其中該經修飾之寡核苷酸為該第二經修飾之寡核苷酸。The compound of claim 42, wherein the modified oligonucleotide is the second modified oligonucleotide.如請求項42之化合物，其中該一或多種TrkB配位體連接至該經修飾之寡核苷酸之5’端。The compound of claim 42, wherein the one or more TrkB ligands are linked to the 5' end of the modified oligonucleotide.如請求項42之化合物，其中該一或多種TrkB配位體連接至該經修飾之寡核苷酸之3’端。The compound of claim 42, wherein the one or more TrkB ligands are linked to the 3' end of the modified oligonucleotide.如請求項42之化合物，其中該一或多種TrkB配位體連接至該經修飾之寡核苷酸之5’端及3’端。The compound of claim 42, wherein the one or more TrkB ligands are linked to the 5' end and the 3' end of the modified oligonucleotide.如請求項42之化合物，其中該一或多種TrkB配位體係選自式I-式XX中之任一者。The compound of claim 42, wherein the one or more TrkB ligands are selected from any one of Formula I to Formula XX.如請求項42至47中任一項之化合物，其中該一或多種脂質連接至該經修飾之寡核苷酸之核苷間鍵聯。The compound of any one of claims 42 to 47, wherein the one or more lipids are linked to the internucleoside linkage of the modified oligonucleotide.如請求項48之化合物，其中該經修飾之寡核苷酸之該核苷間鍵聯係選自式XXI-式XXIV中之任一者。The compound of claim 48, wherein the internucleoside bond of the modified oligonucleotide is selected from any one of Formula XXI to Formula XXIV.如請求項1至49中任一項之化合物，其中該經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。The compound of any one of claims 1 to 49, wherein the modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups.如請求項50之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。The compound of claim 50, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₄ -C₃₀ hydrocarbon chain.如請求項51之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈，視情況其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。The compound of claim 51, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₅ -C₂₀ hydrocarbon chain, and optionally wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chain.如請求項52之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈、飽和或不飽和C₁₇烴鏈、飽和或不飽和C₁₈烴鏈或飽和或不飽和C₂₂烴鏈。The compound of claim 52, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated_C16 hydrocarbon chain, a saturated or unsaturated_C17 hydrocarbon chain, a saturated or unsaturated_C18 hydrocarbon chain or a saturated or unsaturated_C22 hydrocarbon chain.如請求項50至53中任一項之化合物，其中該一或多個經取代或未經取代之烷基或烯基連接至該經修飾之寡核苷酸之核苷間鍵聯。The compound of any one of claims 50 to 53, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to the internucleoside linkage of the modified oligonucleotide.如請求項54之化合物，其中該經修飾之寡核苷酸之該核苷間鍵聯係選自式XXI-式XXIV中之任一者。The compound of claim 54, wherein the internucleoside bond of the modified oligonucleotide is selected from any one of Formula XXI to Formula XXIV.如請求項1至6中任一項之化合物，其中該經修飾之寡核苷酸包含5'-膦酸酯修飾。The compound of any one of claims 1 to 6, wherein the modified oligonucleotide comprises a 5'-phosphonate modification.如請求項7至55中任一項之化合物，其中該第一經修飾之寡核苷酸包含5'-膦酸酯修飾。The compound of any one of claims 7 to 55, wherein the first modified oligonucleotide comprises a 5'-phosphonate modification.如請求項56或57之化合物，其中該5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。The compound of claim 56 or 57, wherein the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylephosphonate modification.一種化合物，其包含： 包含5'-膦酸酯修飾之第一經修飾之寡核苷酸，其中該第一經修飾之寡核苷酸與SEQ ID NO: 1或2之區域至少80%互補；及 包含一或多種配位體之第二經修飾之寡核苷酸。A compound comprising:a first modified oligonucleotide comprising a 5'-phosphonate modification, wherein the first modified oligonucleotide is at least 80% complementary to a region of SEQ ID NO: 1 or 2; anda second modified oligonucleotide comprising one or more ligands.如請求項59之化合物，其中該第一經修飾之寡核苷酸包含含有該5'-膦酸酯修飾之5'末端核苷。The compound of claim 59, wherein the first modified oligonucleotide comprises a 5'-terminal nucleoside comprising the 5'-phosphonate modification.如請求項59或60之化合物，其中該5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾或5'-伸乙基膦酸酯修飾。The compound of claim 59 or 60, wherein the 5'-phosphonate modification is a 5'-vinylphosphonate modification or a 5'-ethylephosphonate modification.如請求項59至61中任一項之化合物，其中該5'-膦酸酯修飾為5'-乙烯基膦酸酯修飾。The compound of any one of claims 59 to 61, wherein the 5'-phosphonate modification is a 5'-vinylphosphonate modification.如請求項59至61中任一項之化合物，其中該5'-膦酸酯修飾為5'-伸乙基膦酸酯修飾。The compound of any one of claims 59 to 61, wherein the 5'-phosphonate modification is a 5'-ethylephosphonate modification.如請求項59至63中任一項之化合物，其中該第二經修飾之寡核苷酸之該一或多種配位體包含一或多種TrkB配位體。A compound as in any one of claims 59 to 63, wherein the one or more ligands of the second modified oligonucleotide comprise one or more TrkB ligands.如請求項64之化合物，其中該一或多種TrkB配位體連接至該第二經修飾之寡核苷酸之5’端。The compound of claim 64, wherein the one or more TrkB ligands are linked to the 5' end of the second modified oligonucleotide.如請求項64之化合物，其中該一或多種TrkB配位體連接至該第二經修飾之寡核苷酸之3’端。The compound of claim 64, wherein the one or more TrkB ligands are linked to the 3' end of the second modified oligonucleotide.如請求項64之化合物，其中該一或多種TrkB配位體連接至該第二經修飾之寡核苷酸之5’端及3’端。A compound as claimed in claim 64, wherein the one or more TrkB ligands are linked to the 5' end and the 3' end of the second modified oligonucleotide.如請求項64之化合物，其中該一或多種TrkB配位體係選自式I-式XX中之任一者。The compound of claim 64, wherein the one or more TrkB ligands are selected from any one of Formula I to Formula XX.如請求項64至68中任一項之化合物，其中該第二經修飾之寡核苷酸包含一種TrkB配位體。The compound of any one of claims 64 to 68, wherein the second modified oligonucleotide comprises a TrkB ligand.如請求項64至68中任一項之化合物，其中該第二經修飾之寡核苷酸包含至少兩種TrkB配位體。The compound of any one of claims 64 to 68, wherein the second modified oligonucleotide comprises at least two TrkB ligands.如請求項70之化合物，其中該至少兩種TrkB配位體係相同的。The compound of claim 70, wherein the at least two TrkB ligands are the same.如請求項70之化合物，其中該至少兩種TrkB配位體係不同的。The compound of claim 70, wherein the at least two TrkB ligands are different.如請求項59至72中任一項之化合物，其中該第二經修飾之寡核苷酸包含一或多種脂質。The compound of any one of claims 59 to 72, wherein the second modified oligonucleotide comprises one or more lipids.如請求項59至73中任一項之化合物，其中該第二經修飾之寡核苷酸包含一或多個經取代或未經取代之烷基或烯基。The compound of any one of claims 59 to 73, wherein the second modified oligonucleotide comprises one or more substituted or unsubstituted alkyl or alkenyl groups.如請求項74之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₄-C₃₀烴鏈。The compound of claim 74, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₄ -C₃₀ hydrocarbon chain.如請求項75之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₅-C₂₀烴鏈，視情況其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₄-C₂₀烴鏈。The compound of claim 75, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₅ -C₂₀ hydrocarbon chain, and optionally wherein the one or more substituted or unsubstituted alkyl or alkenyl groups contain a saturated or unsaturated C₁₄ -C₂₀ hydrocarbon chain.如請求項76之化合物，其中該一或多個經取代或未經取代之烷基或烯基包含飽和或不飽和C₁₆烴鏈、飽和或不飽和C₁₇烴鏈、飽和或不飽和C₁₈烴鏈或飽和或不飽和C₂₂烴鏈。The compound of claim 76, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups comprise a saturated or unsaturated_C16 hydrocarbon chain, a saturated or unsaturated_C17 hydrocarbon chain, a saturated or unsaturated_C18 hydrocarbon chain or a saturated or unsaturated_C22 hydrocarbon chain.如請求項74至77中任一項之化合物，其中該一或多個經取代或未經取代之烷基或烯基連接至該第二經修飾之寡核苷酸之核苷間鍵聯。The compound of any one of claims 74 to 77, wherein the one or more substituted or unsubstituted alkyl or alkenyl groups are linked to the internucleoside linkage of the second modified oligonucleotide.如請求項78之化合物，其中該第二經修飾之寡核苷酸之該核苷間鍵聯係選自式XXI-式XXIV中之任一者。The compound of claim 78, wherein the internucleoside bond of the second modified oligonucleotide is selected from any one of Formula XXI to Formula XXIV.如請求項59至79中任一項之化合物，其中該第一經修飾之寡核苷酸之長度為14至30個連接核苷。The compound of any one of claims 59 to 79, wherein the first modified oligonucleotide has a length of 14 to 30 linked nucleosides.如請求項59至80中任一項之化合物，其中該第二經修飾之寡核苷酸之長度為14至30個連接核苷，其具有與該第一經修飾之寡核苷酸互補之區域。A compound as in any one of claims 59 to 80, wherein the second modified oligonucleotide is 14 to 30 linked nucleosides in length and has a region complementary to the first modified oligonucleotide.如請求項59至81中任一項之化合物，其中該第一經修飾之寡核苷酸具有包含SEQ ID NO: 11-44及83-89中之任一者之至少14個鄰接核鹼基之核鹼基序列。The compound of any one of claims 59 to 81, wherein the first modified oligonucleotide has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 11-44 and 83-89.如請求項59至82中任一項之化合物，其中該第二經修飾之寡核苷酸具有包含SEQ ID NO: 45-82及90-96中之任一者之至少14個鄰接核鹼基之核鹼基序列。The compound of any one of claims 59 to 82, wherein the second modified oligonucleotide has a nucleobase sequence comprising at least 14 adjacent nucleobases of any one of SEQ ID NOs: 45-82 and 90-96.如請求項59至83中任一項之化合物，其中該第一經修飾之寡核苷酸係選自表3中IA Ref ID NO中之任一者。The compound of any one of claims 59 to 83, wherein the first modified oligonucleotide is selected from any one of IA Ref ID NOs in Table 3.如請求項59至84中任一項之化合物，其中該第二經修飾之寡核苷酸係選自表3中IS Ref ID NO中之任一者。The compound of any one of claims 59 to 84, wherein the second modified oligonucleotide is selected from any one of the IS Ref ID NOs in Table 3.一種化合物，其包含選自由表3中IA Ref ID NO中之任一者組成之群的第一經修飾之寡核苷酸，及與該第一經修飾之寡核苷酸完全互補的長度為14至21個連接核苷之第二經修飾之寡核苷酸。A compound comprising a first modified oligonucleotide selected from the group consisting of any one of IA Ref ID NOs in Table 3, and a second modified oligonucleotide having a length of 14 to 21 linked nucleosides that is completely complementary to the first modified oligonucleotide.一種化合物，其包含選自由表3中IA Ref ID NO中之任一者組成之群的第一經修飾之寡核苷酸及選自由表3中IS Ref ID NO中之任一者組成之群的第二經修飾之寡核苷酸。A compound comprising a first modified oligonucleotide selected from the group consisting of any one of IA Ref ID NOs in Table 3 and a second modified oligonucleotide selected from the group consisting of any one of IS Ref ID NOs in Table 3.一種化合物，其包含選自由表3中IA Ref ID NO中之任一者組成之群的第一經修飾之寡核苷酸及選自由表3中IS Ref ID NO中之任一者組成之群的第二經修飾之寡核苷酸。A compound comprising a first modified oligonucleotide selected from the group consisting of any one of IA Ref ID NOs in Table 3 and a second modified oligonucleotide selected from the group consisting of any one of IS Ref ID NOs in Table 3.如請求項86、87或88之化合物，其包含結合基團。The compound of claim 86, 87 or 88, comprising a binding group.如請求項89之化合物，其中該結合基團連接至該經修飾之寡核苷酸之5’端。A compound as claimed in claim 89, wherein the binding group is linked to the 5' end of the modified oligonucleotide.如請求項89或90之化合物，其中該結合基團包含靶向部分。A compound as claimed in claim 89 or 90, wherein the binding group comprises a targeting moiety.如請求項91之化合物，其中該靶向部分包含一或多種原肌凝蛋白受體B (TrkB)配位體。A compound as claimed in claim 91, wherein the targeting portion comprises one or more tropomyosin receptor B (TrkB) ligands.如請求項92之化合物，其中該經修飾之寡核苷酸為該第二經修飾之寡核苷酸。The compound of claim 92, wherein the modified oligonucleotide is the second modified oligonucleotide.如請求項93之化合物，其中該一或多種TrkB配位體連接至該經修飾之寡核苷酸之5’端。The compound of claim 93, wherein the one or more TrkB ligands are linked to the 5' end of the modified oligonucleotide.如請求項93之化合物，其中該一或多種TrkB配位體連接至該經修飾之寡核苷酸之3’端。The compound of claim 93, wherein the one or more TrkB ligands are linked to the 3' end of the modified oligonucleotide.如請求項93之化合物，其中該一或多種TrkB配位體連接至該經修飾之寡核苷酸之5’端及3’端。The compound of claim 93, wherein the one or more TrkB ligands are linked to the 5' end and the 3' end of the modified oligonucleotide.如請求項93之化合物，其中該一或多種TrkB配位體係選自式I-式XX中之任一者。The compound of claim 93, wherein the one or more TrkB ligands are selected from any one of Formula I to Formula XX.如請求項1至97中任一項之化合物，其中該化合物係呈醫藥學上可接受之鹽形式。The compound of any one of claims 1 to 97, wherein the compound is in the form of a pharmaceutically acceptable salt.如請求項98之化合物，其中該醫藥學上可接受之鹽為鈉鹽。The compound of claim 98, wherein the pharmaceutically acceptable salt is a sodium salt.如請求項98之化合物，其中該醫藥學上可接受之鹽為鉀鹽。The compound of claim 98, wherein the pharmaceutically acceptable salt is a potassium salt.一種組合物，其包含如任一前述請求項之化合物或經修飾之寡核苷酸以及醫藥學上可接受之載劑。A composition comprising a compound or modified oligonucleotide as claimed in any preceding claim and a pharmaceutically acceptable carrier.一種用於療法中之組合物，其包含如任一前述請求項之化合物或經修飾之寡核苷酸。A composition for use in therapy, comprising a compound or modified oligonucleotide as claimed in any preceding claim.一種治療、預防或改善個體之與LRRK2相關之疾病、病症或疾患之方法，其包括向該個體投與靶向LRRK2之化合物，藉此治療、預防或改善該疾病、病症或疾患。A method for treating, preventing or ameliorating a disease, disorder or condition associated with LRRK2 in a subject, comprising administering a compound targeting LRRK2 to the subject, thereby treating, preventing or ameliorating the disease, disorder or condition.一種向個體投與如請求項1至100中任一項之化合物或經修飾之寡核苷酸或如請求項102之組合物的方法。A method of administering the compound or modified oligonucleotide of any one of claims 1 to 100 or the composition of claim 102 to a subject.如請求項103或104之方法，其中該疾病、病症或疾患為神經退化性疾病，包括帕金森氏病(Parkinson’s Disease)或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。The method of claim 103 or 104, wherein the disease, disorder or condition is a neurodegenerative disease, including Parkinson's Disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation and neuronal death.如請求項103至105中任一項之方法，其中投與該化合物抑制或減少或改進神經退化性疾病，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。The method of any one of claims 103 to 105, wherein administration of the compound inhibits or reduces or ameliorates neurodegenerative diseases, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation and neuronal death.一種抑制細胞中之LRRK2表現之方法，其包括使該細胞與靶向LRRK2之化合物接觸，藉此抑制該細胞中之LRRK2表現。A method for inhibiting LRRK2 expression in a cell, comprising contacting the cell with a compound targeting LRRK2, thereby inhibiting LRRK2 expression in the cell.如請求項107之方法，其中該細胞係在個體之腦中。The method of claim 107, wherein the cell is in the brain of the individual.如請求項108之方法，其中該個體患有神經退化性疾病，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡，或處於患有此類疾病之風險下。The method of claim 108, wherein the individual has, or is at risk of having, a neurodegenerative disease including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation, and neuronal death.一種減少或抑制個體之神經退化性疾病、包括帕金森氏病或認知損害或其症狀、諸如運動功能喪失、聚集體形成及神經元死亡之方法，其包括向該個體投與靶向LRRK2之化合物，藉此減少或抑制該個體之神經退化性疾病，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。A method for reducing or inhibiting a neurodegenerative disease, including Parkinson's disease or cognitive impairment or symptoms thereof, such as motor function loss, aggregate formation and neuronal death, in a subject, comprising administering to the subject a compound targeting LRRK2, thereby reducing or inhibiting a neurodegenerative disease, including Parkinson's disease or cognitive impairment or symptoms thereof, such as motor function loss, aggregate formation and neuronal death, in the subject.如請求項110之方法，其中該個體患有神經退化性疾病，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡，或處於患有此類疾病之風險下。The method of claim 110, wherein the individual has, or is at risk of having, a neurodegenerative disease including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation, and neuronal death.如請求項103至111中任一項之方法，其中該化合物為靶向LRRK2之化合物。The method of any one of claims 103 to 111, wherein the compound is a compound targeting LRRK2.如請求項103至112中任一項之方法，其中該化合物或該經修飾之寡核苷酸為如請求項1至100中任一項之化合物或經修飾之寡核苷酸或如請求項102之組合物。The method of any one of claims 103 to 112, wherein the compound or the modified oligonucleotide is the compound or modified oligonucleotide of any one of claims 1 to 100 or the composition of claim 102.如請求項113之方法，其中非經腸投與該化合物或該組合物。The method of claim 113, wherein the compound or the composition is administered parenterally.如請求項113之方法，其中藉由鞘內投與來投與該化合物或該組合物。The method of claim 113, wherein the compound or the composition is administered by intrathecal administration.一種靶向LRRK2之化合物之用途，其用於治療、預防或改善與LRRK2相關之疾病、病症或疾患。A use of a compound targeting LRRK2 for treating, preventing or ameliorating a disease, disorder or condition associated with LRRK2.如請求項116之用途，其中該疾病、病症或疾患為神經退化性疾病，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。The use of claim 116, wherein the disease, disorder or condition is a neurodegenerative disease, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation and neuronal death.如請求項116或117之用途，其中該化合物為靶向LRRK2之化合物。The use of claim 116 or 117, wherein the compound is a compound targeting LRRK2.如請求項116至118中任一項之用途，其中該化合物或該經修飾之寡核苷酸為如請求項1至100中任一項之化合物或經修飾之寡核苷酸或如請求項102之組合物。The use of any one of claims 116 to 118, wherein the compound or the modified oligonucleotide is the compound or modified oligonucleotide of any one of claims 1 to 100 or the composition of claim 102.一種靶向LRRK2之化合物之用途，其用於製造用以治療、預防或改善與LRRK2相關之疾病、病症或疾患的藥劑。A use of a compound targeting LRRK2 for manufacturing a medicament for treating, preventing or ameliorating a disease, disorder or condition associated with LRRK2.如請求項120之用途，其中該疾病為神經退化性疾病，包括帕金森氏病或認知損害或其症狀，諸如運動功能喪失、聚集體形成及神經元死亡。The use of claim 120, wherein the disease is a neurodegenerative disease, including Parkinson's disease or cognitive impairment or symptoms thereof, such as loss of motor function, aggregate formation and neuronal death.如請求項120或121之用途，其中該化合物為靶向LRRK2之化合物。The use of claim 120 or 121, wherein the compound is a compound targeting LRRK2.如請求項120至122中任一項之用途，其中該化合物或該經修飾之寡核苷酸為如請求項1至100中任一項之化合物或經修飾之寡核苷酸或如請求項102之組合物。The use of any one of claims 120 to 122, wherein the compound or the modified oligonucleotide is the compound or modified oligonucleotide of any one of claims 1 to 100 or the composition of claim 102.如任一前述請求項之方法或用途，其中約每三個月一次至約每年一次向個體投與該化合物或該組合物。The method or use of any preceding claim, wherein the compound or the composition is administered to the subject about once every three months to about once a year.如任一前述請求項之方法或用途，其中約每三個月一次、約每六個月一次或約每年一次向個體投與該化合物或該組合物。The method or use of any preceding claim, wherein the compound or the composition is administered to the subject about once every three months, about once every six months, or about once a year.一種向個體之腦遞送治療性寡核苷酸之方法，該方法包括向該個體投與如請求項1至100中任一項之化合物或其立體異構物、互變異構物、前藥或鹽或如請求項102之組合物。A method for delivering a therapeutic oligonucleotide to the brain of a subject, the method comprising administering to the subject a compound of any one of claims 1 to 100 or a stereoisomer, tautomer, prodrug or salt thereof, or a composition of claim 102.如請求項126之方法，其中將該治療性寡核苷酸遞送至一或多個選自由以下組成之群的腦區域：紋狀體、小腦、腦幹、海馬體、額葉皮質及脊髓。The method of claim 126, wherein the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of striatum, cerebellum, brain stem, hippocampus, frontal cortex, and spinal cord.一種治療或改善個體之疾病、病症或其症狀之方法，該方法包括向該個體投與如請求項1至100中任一項之化合物或其立體異構物、互變異構物、前藥或鹽或如請求項102之組合物。A method for treating or ameliorating a disease, disorder or symptom thereof in a subject, the method comprising administering to the subject a compound of any one of claims 1 to 100 or a stereoisomer, tautomer, prodrug or salt thereof, or a composition of claim 102.如請求項128之方法，其中該疾病、病症或其症狀為中樞神經系統(CNS)疾病、病症或其症狀。The method of claim 128, wherein the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof.如請求項128或129之方法，其中該疾病、病症或其症狀為阿茲海默氏病(Alzheimer’s disease)或其症狀。The method of claim 128 or 129, wherein the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof.如請求項126至130中任一項之方法，其中該投與為鞘內投與或腦室內(ICV)投與。The method of any one of claims 126 to 130, wherein the administration is intrathecal administration or intracerebroventricular (ICV) administration.一種向個體之細胞或組織活體內遞送一或多種貨物分子之方法，其包括向該個體投與如請求項1至100中任一項之化合物或如請求項102之組合物。A method for delivering one or more cargo molecules into cells or tissues of a subject in vivo, comprising administering to the subject a compound of any one of claims 1 to 100 or a composition of claim 102.如請求項132之方法，其中該細胞或組織為CNS細胞或組織。The method of claim 132, wherein the cell or tissue is a CNS cell or tissue.