CN118401666A - Antisense oligonucleotides targeting ATN1 mRNA or pre-mRNA - Google Patents

Abstract

In the present specification, an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof, which is composed of 15 to 22 nucleotides and is complementary to a nucleic acid of at least 15 consecutive bases in a specific target region comprising a base sequence of SEQ ID NO. 471, is provided.

Description

Translated fromChinese

靶向ATN1 mRNA或pre-mRNA的反义寡核苷酸Antisense oligonucleotides targeting ATN1 mRNA or pre-mRNA

技术领域Technical Field

本发明涉及靶向ATN1 mRNA或pre-mRNA的反义寡核苷酸或其药物上可接受的盐或者它们的水合物、包含该反义寡核苷酸或其药物上可接受的盐或者它们的水合物的药物组合物等。The present invention relates to an antisense oligonucleotide targeting ATN1 mRNA or pre-mRNA or a pharmaceutically acceptable salt or a hydrate thereof, a pharmaceutical composition comprising the antisense oligonucleotide or a pharmaceutically acceptable salt or a hydrate thereof, and the like.

背景技术Background technique

齿状核红核苍白球路易体萎缩症(DRPLA)是儿童的情况下会发生共济失调、称为肌阵挛(myoclonus)的不自主运动、癫痫和进行性智力退化等、成人的情况下会发生共济失调、舞蹈徐动症(choreoathetosis)、痴呆症或性格改变等的进行性疾病(非专利文献1)。Dentatorubral pallidum atrophy (DRPLA) is a progressive disease that causes ataxia, involuntary movements called myoclonus, epilepsy, and progressive mental retardation in children, and ataxia, choreoathetosis, dementia, or personality changes in adults (Non-Patent Document 1).

DRPLA是存在于特定基因的基因组中的重复序列异常延伸、从而RNA、蛋白质的功能发生异常而发生的疾病(重复病)。已知DRPLA是重复病中蛋白质显示出毒性的疾病。DRPLA根据发病时期可分为20岁后发病的成人型和20岁前发病的儿童型，重复次数为约65以上的患者为早期发病的儿童型，病情相对严重。DRPLA is a disease (repetitive disease) caused by abnormal extension of the repetitive sequence present in the genome of a specific gene, resulting in abnormal functions of RNA and protein. DRPLA is known to be a disease in which proteins show toxicity among repetitive diseases. DRPLA can be divided into adult type that develops after the age of 20 and pediatric type that develops before the age of 20 according to the onset period. Patients with more than 65 repetitions are early-onset pediatric type, and the condition is relatively serious.

目前，对于DRPLA症状中的癫痫、精神症状、共济失调等，虽然存在对症疗法药物，但是其治疗满意度低，且无法应对作为DRPLA基础的分子机制。Currently, although there are symptomatic treatment drugs for epilepsy, psychiatric symptoms, ataxia, etc. among the symptoms of DRPLA, the treatment satisfaction is low and they cannot address the molecular mechanism that is the basis of DRPLA.

现有技术文献Prior art literature

非专利文献Non-patent literature

非专利文献1：Liana Veneziano et al.,GeneReviews[Internet]1999Aug 6[updated 2016Jun 9],1993-2021.Non-patent literature 1: Liana Veneziano et al., Gene Reviews [Internet] 1999 Aug 6 [updated 2016 Jun 9], 1993-2021.

发明内容Summary of the invention

在这种状况下，期望提供发挥更优异的治疗效果的DRPLA治疗剂。Under such circumstances, it is desired to provide a DRPLA therapeutic agent that exerts a more excellent therapeutic effect.

本发明提供以下记载的靶向ATN1 mRNA或pre-mRNA的反义寡核苷酸或其药物上可接受的盐或者它们的水合物、包含该反义寡核苷酸或其药物上可接受的盐或者它们的水合物的药物组合物等。The present invention provides the following antisense oligonucleotides targeting ATN1 mRNA or pre-mRNA, or pharmaceutically acceptable salts thereof, or hydrates thereof, and pharmaceutical compositions comprising the antisense oligonucleotides, or pharmaceutically acceptable salts thereof, or hydrates thereof.

(1-1)一种反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1位～第84位、第142位～第168位、第197位～第224位、第286位～第317位、第324位～第370位、第391位～第434位、第519位～第540位、第623位～第643位、第690位～第780位、第824位～第855位、第860位～第897位、第948位～第987位、第1044位～第1072位、第1125位～第1174位、第1181位～第1213位、第1228位～第1255位、第1265位～第1327位、第1334位～第1356位、第1416位～第1440位、第1447位～第1631位、第1638位～第1667位、第1675位～第1705位、第1748位～第1823位、第1838位～第1861位、第1870位～第1913位、第1920位～第1941位、第2000位～第2040位、第2047位～第2075位、第2086位～第2120位、第2129位～第2187位、第2194位～第2415位、第2451位～第2497位、第2592位～第2759位、第2766位～第2870位、第2928位～第2948位、第2955位～第2989位、第3021位～第3086位、第3133位～第3209位、第3217位～第3284位、第3295位～第3350位、第3384位～第3436位、第3562位～第3771位、第3858位～第3905位、第3931位～第4039位、第4067位～第4134位、第4170位～第4232位、第4241位～第4283位和第4286位～第4355位组成的组中的靶区域中的至少15个连续的碱基。(1-1) An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof, which is composed of 15 to 22 nucleotides and is complementary to the following nucleic acid, wherein the nucleic acid comprises: a base sequence selected from positions 1 to 84, 142 to 168, 197 to 224, 286 to 317, 324 to 370, 391 to 434, 519 to 540, 623 to 643, 690 to 780, 824 to 865, 876 to 880, 891 to 914, 927 to 933, 940 to 951, 961 to 971, 981 to 993, 994 to 1003, 995 to 1015, 996 to 1024, 997 to 1035, 998 to 1043, 999 to 1054, 999 to 1064, 999 to 1071, 999 to 1081, 999 to 1093, 999 to 1104, 999 to 1115 855th, 860th - 897th, 948th - 987th, 1044th - 1072nd, 1125th - 1174th, 1181st - 1213th, 1228th - 1255th, 1265th - 1327th, 1334th - 1356th, 1416th - 1440th, 1447th - 1631st, 1638th - 1667th, 1675th - 1705th, 1748th - 1823rd, 1838th to 1861st, 1870th to 1913th, 1920th to 1941st, 2000th to 2040th, 2047th to 2075th, 2086th to 2120th, 2129th to 2187th, 2194th to 2415th, 2451st to 2497th, 2592nd to 2759th, 2766th to 2870th, 2928th to 2948th, 2955th to 2989th, 30 At least 15 consecutive bases in the target region in the group consisting of positions 21 to 3086, 3133 to 3209, 3217 to 3284, 3295 to 3350, 3384 to 3436, 3562 to 3771, 3858 to 3905, 3931 to 4039, 4067 to 4134, 4170 to 4232, 4241 to 4283 and 4286 to 4355.

(1-2)根据(1-1)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1位～第84位、第142位～第168位、第391位～第434位、第697位～第780位、第962位～第980位、第1125位～第1174位、第1181位～第1213位、第1228位～第1255位、第1265位～第1320位、第1454位～第1631位、第1682位～第1705位、第1748位～第1816位、第1870位～第1913位、第2015位～第2040位、第2086位～第2120位、第2129位～第2187位、第2201位～第2408位、第2592位～第2759位、第2773位～第2870位、第2955位～第2982位、第3028位～第3079位、第3133位～第3209位、第3224位～第3277位、第3295位～第3350位、第3391位～第3429位、第3562位～第3771位、第3865位～第3898位、第3938位～第4032位、第4074位～第4127位和第4170位～第4225位组成的组中的靶区域中的至少15个连续的碱基。(1-2) The antisense oligonucleotide according to (1-1), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 1 to 84, 142 to 168, 391 to 434, 697 to 780, 962 to 980, 1125 to 1174, 1181 to 1213, 1228 to 1255, 1265 to 1320, 1454 to 1631, 1682 to 1705, 1748 to 1816, 1870 to 1913, 2015 to 2 040, 2086-2120, 2129-2187, 2201-2408, 2592-2759, 2773-2870, 2955-2982, 3028-3079, 3133-3209, 3224-3277, 3295-3350, 3391-3429, 3562-3771, 3865-3898, 3938-4032, 4074-4127 and 4170-4225.

(2-1)根据(1-1)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1位～第69位、第331位～第363位、第398位～第427位、第697位～第773位、第867位～第890位、第955位～第980位、第1132位～第1167位、第1272位～第1320位、第1454位～第1624位、第1682位～第1705位、第1748位～第1816位、第1877位～第1906位、第2007位～第2033位、第2093位～第2113位、第2136位～第2180位、第2201位～第2408位、第2458位～第2490位、第2599位～第2752位、第2773位～第2863位、第2962位～第2982位、第3028位～第3079位、第3140位～第3202位、第3224位～第3277位、第3302位～第3343位、第3391位～第3429位、第3569位～第3764位、第3865位～第3898位、第3938位～第4032位、第4074位～第4127位、第4177位～第4225位、第4248位～第4276位和第4293位～第4355位组成的组中的靶区域中的至少15个连续的碱基。(2-1) The antisense oligonucleotide according to (1-1), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 1 to 69, 331 to 363, 398 to 427, 697 to 773, 867 to 890, 955 to 980, 1132 to 1167, 1272 to 1320, 1454 to 1624, 1682 to 1705, 1748 to 1816, 1877 to 1906, 2007 to 2033, 2093 to 2113, 2136 to 2143, 80th, 2201st to 2408th, 2458th to 2490th, 2599th to 2752nd, 2773rd to 2863rd, 2962nd to 2982nd, 3028th to 3079th, 3140th to 3202nd, 3224th to 3277th, 3302nd to 3343rd, At least 15 consecutive bases in the target region of the group consisting of positions 3391 to 3429, positions 3569 to 3764, positions 3865 to 3898, positions 3938 to 4032, positions 4074 to 4127, positions 4177 to 4225, positions 4248 to 4276, and positions 4293 to 4355.

(2-2)根据(1-1)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1位～第69位、第398位～第427位、第697位～第773位、第1132位～第1167位、第1272位～第1320位、第1454位～第1624位、第1682位～第1705位、第1748位～第1816位、第1877位～第1906位、第2093位～第2113位、第2136位～第2180位、第2201位～第2408位、第2599位～第2752位、第2773位～第2863位、第2962位～第2982位、第3028位～第3079位、第3140位～第3202位、第3224位～第3277位、第3302位～第3343位、第3391位～第3429位、第3569位～第3764位、第3865位～第3898位、第3938位～第4032位和第4177位～第4225位组成的组中的靶区域中的至少15个连续的碱基。(2-2) The antisense oligonucleotide according to (1-1), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 1 to 69, positions 398 to 427, positions 697 to 773, positions 1132 to 1167, positions 1272 to 1320, positions 1454 to 1624, positions 1682 to 1705, positions 1748 to 1816, positions 1877 to 1906, positions 2093 to 2113, positions 2136 to 2143, positions 2157 to 2164, positions 2216 to 2277, positions 2284 to 2291, positions 2303 to 2313, positions 2314 to 2327, positions 2328 to 2333, positions 2336 to 2345, positions 2347 to 2366, positions 2368 to 2370, positions 2371 to 2381 At least 15 consecutive bases in the target region in the group consisting of positions 2180, 2201 to 2408, 2599 to 2752, 2773 to 2863, 2962 to 2982, 3028 to 3079, 3140 to 3202, 3224 to 3277, 3302 to 3343, 3391 to 3429, 3569 to 3764, 3865 to 3898, 3938 to 4032, and 4177 to 4225.

(3)根据(1-1)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第54位～第73位、第148位～第167位、第397位～第432位、第723位～第742位、第747位～第778位、第965位～第984位、第1127位～第1146位、第1148位～第1173位、第1182位～第1213位、第1228位～第1254位、第1270位～第1308位、第1484位～第1564位、第1578位～第1629位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1870位～第1913位、第2015位～第2034位、第2086位～第2118位、第2129位～第2148位、第2151位～第2184位、第2206位～第2225位、第2239位～第2272位、第2287位～第2336位、第2337位～第2373位、第2387位～第2406位、第2598位～第2757位、第2775位～第2809位、第2826位～第2866位、第2959位～第2982位、第3032位～第3051位、第3052位～第3071位、第3136位～第3155位、第3168位～第3187位、第3188位～第3207位、第3232位～第3270位、第3298位～第3344位、第3408位～第3427位、第3563位～第3582位、第3590位～第3728位、第3739位～第3769位、第3877位～第3896位、第3949位～第4030位和第4170位～第4225位组成的组中的靶区域中的至少15个连续的碱基。(3) The antisense oligonucleotide according to (1-1), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 14 to 33, positions 34 to 53, positions 54 to 73, positions 148 to 167, positions 397 to 432, positions 723 to 742, positions 747 to 778, positions 965 to 984, positions 1127 to 1146, positions 1148 to 167 ...8, positions 397 to 432, positions 723 to 742, positions 747 to 778, positions 965 to 984, positions 1127 to 1146, positions 1148 to 1679, positions 397 to 432, positions 723 to 742, positions 747 to 778, positions 965 to 984, positions 1127 to 1146, positions 1148 to 1173rd, 1182nd to 1213th, 1228th to 1254th, 1270th to 1308th, 1484th to 1564th, 1578th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1913th, 2015th to 2034th, 2086th to 2118th, 2129th to 2148th, 2151st to 2184th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2598th to 2757th, 2775th to 2809th, 2826th to 2866th, 2959th to 2982nd, 3032nd to 3051st, 3052nd to 3071st, 3136th to At least 15 consecutive bases in the target region in the group consisting of positions 3155, 3168 to 3187, 3188 to 3207, 3232 to 3270, 3298 to 3344, 3408 to 3427, 3563 to 3582, 3590 to 3728, 3739 to 3769, 3877 to 3896, 3949 to 4030 and 4170 to 4225.

(4)根据(3)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第54位～第73位、第148位～第167位、第397位～第416位、第398位～第417位、第399位～第418位、第400位～第419位、第401位～第420位、第402位～第421位、第403位～第422位、第404位～第423位、第405位～第424位、第406位～第425位、第407位～第426位、第408位～第427位、第413位～第432位、第723位～第742位、第747位～第766位、第756位～第775位、第759位～第778位、第965位～第984位、第1127位～第1146位、第1148位～第1167位、第1151位～第1170位、第1154位～第1173位、第1182位～第1201位、第1185位～第1204位、第1188位～第1207位、第1191位～第1210位、第1194位～第1213位、第1228位～第1247位、第1231位～第1250位、第1235位～第1254位、第1270位～第1289位、第1289位～第1308位、第1484位～第1503位、第1488位～第1507位、第1491位～第1510位、第1493位～第1512位、第1506位～第1525位、第1517位～第1536位、第1531位～第1550位、第1545位～第1564位、第1578位～第1597位、第1579位～第1598位、第1580位～第1599位、第1581位～第1600位、第1582位～第1601位、第1583位～第1602位、第1584位～第1603位、第1585位～第1604位、第1586位～第1605位、第1587位～第1606位、第1588位～第1607位、第1589位～第1608位、第1590位～第1609位、第1591位～第1610位、第1592位～第1611位、第1593位～第1612位、第1594位～第1613位、第1595位～第1614位、第1596位～第1615位、第1597位～第1616位、第1598位～第1617位、第1599位～第1618位、第1600位～第1619位、第1601位～第1620位、第1602位～第1621位、第1603位～第1622位、第1604位～第1623位、第1605位～第1624位、第1607位～第1626位、第1610位～第1629位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1870位～第1889位、第1871位～第1890位、第1874位～第1893位、第1877位～第1896位、第1878位～第1897位、第1879位～第1898位、第1880位～第1899位、第1881位～第1900位、第1882位～第1901位、第1883位～第1902位、第1884位～第1903位、第1885位～第1904位、第1886位～第1905位、第1887位～第1906位、第1889位～第1908位、第1894位～第1913位、第2015位～第2034位、第2086位～第2105位、第2093位～第2112位、第2094位～第2113位、第2097位～第2116位、第2099位～第2118位、第2129位～第2148位、第2151位～第2170位、第2165位～第2184位、第2206位～第2225位、第2239位～第2258位、第2253位～第2272位、第2287位～第2306位、第2301位～第2320位、第2317位～第2336位、第2337位～第2356位、第2354位～第2373位、第2387位～第2406位、第2598位～第2617位、第2613位～第2632位、第2614位～第2633位、第2615位～第2634位、第2616位～第2635位、第2617位～第2636位、第2618位～第2637位、第2619位～第2638位、第2620位～第2639位、第2621位～第2640位、第2622位～第2641位、第2623位～第2642位、第2624位～第2643位、第2625位～第2644位、第2626位～第2645位、第2627位～第2646位、第2628位～第2647位、第2629位～第2648位、第2630位～第2649位、第2631位～第2650位、第2632位～第2651位、第2633位～第2652位、第2634位～第2653位、第2635位～第2654位、第2636位～第2655位、第2637位～第2656位、第2638位～第2657位、第2639位～第2658位、第2640位～第2659位、第2641位～第2660位、第2642位～第2661位、第2643位～第2662位、第2644位～第2663位、第2645位～第2664位、第2646位～第2665位、第2647位～第2666位、第2648位～第2667位、第2649位～第2668位、第2663位～第2682位、第2672位～第2691位、第2673位～第2692位、第2674位～第2693位、第2675位～第2694位、第2676位～第2695位、第2677位～第2696位、第2678位～第2697位、第2679位～第2698位、第2680位～第2699位、第2681位～第2700位、第2682位～第2701位、第2683位～第2702位、第2684位～第2703位、第2685位～第2704位、第2686位～第2705位、第2687位～第2706位、第2688位～第2707位、第2689位～第2708位、第2690位～第2709位、第2691位～第2710位、第2692位～第2711位、第2693位～第2712位、第2694位～第2713位、第2695位～第2714位、第2696位～第2715位、第2697位～第2716位、第2698位～第2717位、第2699位～第2718位、第2700位～第2719位、第2701位～第2720位、第2702位～第2721位、第2703位～第2722位、第2704位～第2723位、第2705位～第2724位、第2706位～第2725位、第2707位～第2726位、第2708位～第2727位、第2709位～第2728位、第2710位～第2729位、第2711位～第2730位、第2712位～第2731位、第2713位～第2732位、第2714位～第2733位、第2715位～第2734位、第2716位～第2735位、第2717位～第2736位、第2718位～第2737位、第2719位～第2738位、第2720位～第2739位、第2721位～第2740位、第2722位～第2741位、第2723位～第2742位、第2724位～第2743位、第2725位～第2744位、第2726位～第2745位、第2727位～第2746位、第2728位～第2747位、第2729位～第2748位、第2730位～第2749位、第2731位～第2750位、第2732位～第2751位、第2733位～第2752位、第2738位～第2757位、第2775位～第2794位、第2790位～第2809位、第2826位～第2845位、第2827位～第2846位、第2828位～第2847位、第2829位～第2848位、第2830位～第2849位、第2831位～第2850位、第2832位～第2851位、第2833位～第2852位、第2834位～第2853位、第2835位～第2854位、第2836位～第2855位、第2837位～第2856位、第2838位～第2857位、第2839位～第2858位、第2840位～第2859位、第2841位～第2860位、第2842位～第2861位、第2843位～第2862位、第2844位～第2863位、第2847位～第2866位、第2959位～第2978位、第2962位～第2981位、第2963位～第2982位、第3032位～第3051位、第3052位～第3071位、第3136位～第3155位、第3168位～第3187位、第3188位～第3207位、第3232位～第3251位、第3251位～第3270位、第3298位～第3317位、第3302位～第3321位、第3303位～第3322位、第3304位～第3323位、第3305位～第3324位、第3306位～第3325位、第3307位～第3326位、第3308位～第3327位、第3309位～第3328位、第3310位～第3329位、第3311位～第3330位、第3312位～第3331位、第3313位～第3332位、第3314位～第3333位、第3315位～第3334位、第3316位～第3335位、第3317位～第3336位、第3318位～第3337位、第3319位～第3338位、第3320位～第3339位、第3321位～第3340位、第3322位～第3341位、第3323位～第3342位、第3324位～第3343位、第3325位～第3344位、第3408位～第3427位、第3563位～第3582位、第3590位～第3609位、第3608位～第3627位、第3617位～第3636位、第3618位～第3637位、第3619位～第3638位、第3620位～第3639位、第3621位～第3640位、第3622位～第3641位、第3623位～第3642位、第3624位～第3643位、第3625位～第3644位、第3626位～第3645位、第3627位～第3646位、第3628位～第3647位、第3629位～第3648位、第3630位～第3649位、第3631位～第3650位、第3632位～第3651位、第3633位～第3652位、第3634位～第3653位、第3635位～第3654位、第3636位～第3655位、第3637位～第3656位、第3638位～第3657位、第3639位～第3658位、第3640位～第3659位、第3641位～第3660位、第3642位～第3661位、第3643位～第3662位、第3644位～第3663位、第3645位～第3664位、第3646位～第3665位、第3647位～第3666位、第3648位～第3667位、第3649位～第3668位、第3650位～第3669位、第3651位～第3670位、第3652位～第3671位、第3653位～第3672位、第3654位～第3673位、第3671位～第3690位、第3672位～第3691位、第3673位～第3692位、第3674位～第3693位、第3675位～第3694位、第3676位～第3695位、第3677位～第3696位、第3678位～第3697位、第3679位～第3698位、第3680位～第3699位、第3681位～第3700位、第3682位～第3701位、第3683位～第3702位、第3684位～第3703位、第3685位～第3704位、第3686位～第3705位、第3687位～第3706位、第3688位～第3707位、第3689位～第3708位、第3690位～第3709位、第3691位～第3710位、第3692位～第3711位、第3693位～第3712位、第3694位～第3713位、第3695位～第3714位、第3696位～第3715位、第3697位～第3716位、第3698位～第3717位、第3699位～第3718位、第3700位～第3719位、第3701位～第3720位、第3702位～第3721位、第3703位～第3722位、第3704位～第3723位、第3705位～第3724位、第3706位～第3725位、第3707位～第3726位、第3708位～第3727位、第3709位～第3728位、第3739位～第3758位、第3740位～第3759位、第3741位～第3760位、第3742位～第3761位、第3743位～第3762位、第3744位～第3763位、第3745位～第3764位、第3750位～第3769位、第3877位～第3896位、第3949位～第3968位、第3964位～第3983位、第3965位～第3984位、第3966位～第3985位、第3967位～第3986位、第3968位～第3987位、第3969位～第3988位、第3970位～第3989位、第3971位～第3990位、第3972位～第3991位、第3973位～第3992位、第3974位～第3993位、第3975位～第3994位、第3976位～第3995位、第3977位～第3996位、第3978位～第3997位、第3979位～第3998位、第3980位～第3999位、第3981位～第4000位、第3982位～第4001位、第3983位～第4002位、第3984位～第4003位、第3985位～第4004位、第3986位～第4005位、第3987位～第4006位、第3988位～第4007位、第3989位～第4008位、第3990位～第4009位、第3991位～第4010位、第3992位～第4011位、第3993位～第4012位、第3994位～第4013位、第3995位～第4014位、第3996位～第4015位、第3997位～第4016位、第3998位～第4017位、第3999位～第4018位、第4011位～第4030位、第4170位～第4189位、第4173位～第4192位、第4176位～第4195位、第4177位～第4196位、第4178位～第4197位、第4179位～第4198位、第4180位～第4199位、第4181位～第4200位、第4182位～第4201位、第4183位～第4202位、第4184位～第4203位、第4185位～第4204位、第4186位～第4205位、第4187位～第4206位、第4188位～第4207位、第4189位～第4208位、第4190位～第4209位、第4191位～第4210位、第4192位～第4211位、第4193位～第4212位、第4194位～第4213位、第4195位～第4214位、第4196位～第4215位、第4197位～第4216位、第4198位～第4217位、第4199位～第4218位、第4200位～第4219位、第4201位～第4220位、第4202位～第4221位、第4203位～第4222位、第4204位～第4223位、第4205位～第4224位和第4206位～第4225位组成的组中的靶区域中的至少15个连续的碱基。(4) The antisense oligonucleotide according to (3), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 416, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 424, 2nd, 404th to 423rd, 405th to 424th, 406th to 425th, 407th to 426th, 408th to 427th, 413th to 432nd, 723rd to 742nd, 747th to 766th, 756th to 775th, 759th to 778th, 965th to 984th, 1127th to 1146th, 1148th to 1167th, 1151st to 1170th, 1154th to 1173rd , 1182nd to 1201st, 1185th to 1204th, 1188th to 1207th, 1191st to 1210th, 1194th to 1213th, 1228th to 1247th, 1231st to 1250th, 1235th to 1254th, 1270th to 1289th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 1510th, 1493rd to 1512th, 1506th to 1525th, 1517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1579th to 1598th, 1580th to 1599th, 1581st to 1600th, 1582nd to 1601st, 1583rd to 1602nd, 1584th to 1603rd, 1585th to 1604th, 1586th to 1605th, 1587th to 1606th, 1588th to 1607th, 1589th to 1608th, 1590th to 1609th, 1591st to 1610th, 1592nd to 1611th, 1593rd to 1612th, 1594th to 1613th, 1595th to 1614th, 1596th to 1615th, 1597th to 1616th, 1598th to 1617th, 1599th to 1618th, 1600th to 1 619th, 1601st-1620th, 1602nd-1621st, 1603rd-1622nd, 1604th-1623rd, 1605th-1624th, 1607th-1626th, 1610th-1629th, 1686th-1705th, 1748th-1767th, 1768th-1787th, 1794th-1813th, 1870th-1889th, 1871st-1890th, 18 74th to 1893rd, 1877th to 1896th, 1878th to 1897th, 1879th to 1898th, 1880th to 1899th, 1881st to 1900th, 1882nd to 1901st, 1883rd to 1902nd, 1884th to 1903rd, 1885th to 1904th, 1886th to 1905th, 1887th to 1906th, 1889th to 1908th, 1894th to 191 3rd, 2015th to 2034th, 2086th to 2105th, 2093rd to 2112th, 2094th to 2113th, 2097th to 2116th, 2099th to 2118th, 2129th to 2148th, 2151st to 2170th, 2165th to 2184th, 2206th to 2225th, 2239th to 2258th, 2253rd to 2272nd, 2287th to 2306th, 2301st 2320th, 2317th to 2336th, 2337th to 2356th, 2354th to 2373rd, 2387th to 2406th, 2598th to 2617th, 2613th to 2632nd, 2614th to 2633rd, 2615th to 2634th, 2616th to 2635th, 2617th to 2636th, 2618th to 2637th, 2619th to 2638th, 2620th to 2639th, 2621st to 2640th, 2622nd to 2641st, 2623rd to 2642nd, 2624th to 2643rd, 2625th to 2644th, 2626th to 2645th, 2627th to 2646th, 2628th to 2647th, 2629th to 2648th, 2630th to 2649th, 2631st to 2650th, 2632nd to 2651st, 2633rd to 2652nd, 2634th to 2653rd, 2635th-2654th, 2636th-2655th, 2637th-2656th, 2638th-2657th, 2639th-2658th, 2640th-2659th, 2641st-2660th, 2642nd-2661st, 2643rd-2662nd, 2644th-2663rd, 2645th-2664th, 2646th-2665th, 2647th-2666th, 2650th-2651st 648th to 2667th, 2649th to 2668th, 2663rd to 2682nd, 2672nd to 2691st, 2673rd to 2692nd, 2674th to 2693rd, 2675th to 2694th, 2676th to 2695th, 2677th to 2696th, 2678th to 2697th, 2679th to 2698th, 2680th to 2699th, 2681st to 2700th, 2682nd to 2700th 1st, 2683rd to 2702nd, 2684th to 2703rd, 2685th to 2704th, 2686th to 2705th, 2687th to 2706th, 2688th to 2707th, 2689th to 2708th, 2690th to 2709th, 2691st to 2710th, 2692nd to 2711th, 2693rd to 2712th, 2694th to 2713th, 2695th to 2714th, 2696th 2701-2720, 2702-2721, 2703-2722, 2704-2723, 2705-2724, 2706-2725, 2707-2726, 2708-2727, 2709-2728 , 2710th to 2729th, 2711th to 2730th, 2712th to 2731st, 2713th to 2732nd, 2714th to 2733rd, 2715th to 2734th, 2716th to 2735th, 2717th to 2736th, 2718th to 2737th, 2719th to 2738th, 2720th to 2739th, 2721st to 2740th, 2722nd to 2741st, 2723rd to 2742nd, 2744th to 2743rd, 2725th to 2744th, 2726th to 2745th, 2727th to 2746th, 2728th to 2747th, 2729th to 2748th, 2730th to 2749th, 2731st to 2750th, 2732nd to 2751st, 2733rd to 2752nd, 2738th to 2757th, 2775th to 2794th, 2790th to 2809th, 2 2826th to 2845th, 2827th to 2846th, 2828th to 2847th, 2829th to 2848th, 2830th to 2849th, 2831st to 2850th, 2832nd to 2851st, 2833rd to 2852nd, 2834th to 2853rd, 2835th to 2854th, 2836th to 2855th, 2837th to 2856th, 2838th to 2857th, 2839th to 2840th 58th, 2840th - 2859th, 2841st - 2860th, 2842nd - 2861st, 2843rd - 2862nd, 2844th - 2863rd, 2847th - 2866th, 2959th - 2978th, 2962nd - 2981st, 2963rd - 2982nd, 3032nd - 3051st, 3052nd - 3071st, 3136th - 3155th, 3168th - 3187th, 318 8th to 3207th, 3232nd to 3251st, 3251st to 3270th, 3298th to 3317th, 3302nd to 3321st, 3303rd to 3322nd, 3304th to 3323rd, 3305th to 3324th, 3306th to 3325th, 3307th to 3326th, 3308th to 3327th, 3309th to 3328th, 3310th to 3329th, 3311th to 3330th 3312th to 3331st, 3313th to 3332nd, 3314th to 3333rd, 3315th to 3334th, 3316th to 3335th, 3317th to 3336th, 3318th to 3337th, 3319th to 3338th, 3320th to 3339th, 3321st to 3340th, 3322nd to 3341st, 3323rd to 3342nd, 3324th to 3343rd, 3325th 3344th, 3408th to 3427th, 3563rd to 3582nd, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3618th to 3637th, 3619th to 3638th, 3620th to 3639th, 3621st to 3640th, 3622nd to 3641st, 3623rd to 3642nd, 3624th to 3643rd, 3625th to 3644th, 3626th to 3645th, 3627th to 3646th, 3628th to 3647th, 3629th to 3648th, 3630th to 3649th, 3631st to 3650th, 3632nd to 3651st, 3633rd to 3652nd, 3634th to 3653rd, 3635th to 3654th, 3636th to 3655th, 3637th to 3656th, 3638th to 3657th, 3639th to 3658th, 3640th-3659th, 3641st-3660th, 3642nd-3661st, 3643rd-3662nd, 3644th-3663rd, 3645th-3664th, 3646th-3665th, 3647th-3666th, 3648th-3667th, 3649th-3668th, 3650th-3669th, 3651st-3670th, 3652nd-3671st, 3 653rd to 3672nd, 3654th to 3673rd, 3671st to 3690th, 3672nd to 3691st, 3673rd to 3692nd, 3674th to 3693rd, 3675th to 3694th, 3676th to 3695th, 3677th to 3696th, 3678th to 3697th, 3679th to 3698th, 3680th to 3699th, 3681st to 3700th, 3682nd to 3700th 1st, 3683rd to 3702nd, 3684th to 3703rd, 3685th to 3704th, 3686th to 3705th, 3687th to 3706th, 3688th to 3707th, 3689th to 3708th, 3690th to 3709th, 3691st to 3710th, 3692nd to 3711th, 3693rd to 3712th, 3694th to 3713th, 3695th to 3714th, 3696th 3700-3719th, 3701-3720th, 3702-3721st, 3703-3722nd, 3704-3723rd, 3705-3724th, 3706-3725th, 3707-3726th, 3708-3727th, 3709-3728th , 3739th to 3758th, 3740th to 3759th, 3741st to 3760th, 3742nd to 3761st, 3743rd to 3762nd, 3744th to 3763rd, 3745th to 3764th, 3750th to 3769th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3965th to 3984th, 3966th to 3985th, 3967th to 3986th, 3968th-3987th, 3969th-3988th, 3970th-3989th, 3971st-3990th, 3972nd-3991st, 3973rd-3992nd, 3974th-3993rd, 3975th-3994th, 3976th-3995th, 3977th-3996th, 3978th-3997th, 3979th-3998th, 3980th-3999th, 3981st-3980th 981st to 4000th, 3982nd to 4001st, 3983rd to 4002nd, 3984th to 4003rd, 3985th to 4004th, 3986th to 4005th, 3987th to 4006th, 3988th to 4007th, 3989th to 4008th, 3990th to 4009th, 3991st to 4010th, 3992nd to 4011th, 3993rd to 4012th, 3994th to 4013th 13th, 3995th to 4014th, 3996th to 4015th, 3997th to 4016th, 3998th to 4017th, 3999th to 4018th, 4011th to 4030th, 4170th to 4189th, 4173rd to 4192nd, 4176th to 4195th, 4177th to 4196th, 4178th to 4197th, 4179th to 4198th, 4180th to 4199th, 4181st to 4183rd 1st to 4200th, 4182nd to 4201st, 4183rd to 4202nd, 4184th to 4203rd, 4185th to 4204th, 4186th to 4205th, 4187th to 4206th, 4188th to 4207th, 4189th to 4208th, 4190th to 4209th, 4191st to 4210th, 4192nd to 4211th, 4193rd to 4212th, 4194th to 4213th , 4195-4214, 4196-4215, 4197-4216, 4198-4217, 4199-4218, 4200-4219, 4201-4220, 4202-4221, 4203-4222, 4204-4223, 4205-4224 and 4206-4225.

(5)根据(2-1)或(3)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第398位～第427位、第723位～第742位、第747位～第766位、第1148位～第1167位、第1289位～第1308位、第1484位～第1564位、第1578位～第1624位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1877位～第1906位、第2093位～第2113位、第2151位～第2170位、第2206位～第2225位、第2239位～第2272位、第2287位～第2336位、第2337位～第2373位、第2387位～第2406位、第2613位～第2752位、第2775位～第2809位、第2826位～第2863位、第2962位～第2982位、第3032位～第3051位、第3052位～第3071位、第3168位～第3187位、第3232位～第3270位、第3302位～第3343位、第3408位～第3427位、第3590位～第3728位、第3739位～第3764位、第3877位～第3896位、第3949位～第4030位和第4177位～第4225位组成的组中的靶区域中的至少15个连续的碱基。(5) The antisense oligonucleotide according to (2-1) or (3), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: a base sequence selected from the 14th to 33rd, 34th to 53rd, 398th to 427th, 723rd to 742nd, 747th to 766th, 1148th to 1167th, 12 89th to 1308th, 1484th to 1564th, 1578th to 1624th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1906th, 2093rd to 2113th, 2151st to 2170th, 2206th to 2 225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2613th to 2752nd, 2775th to 2809th, 2826th to 2863rd, 2962nd to 2982nd, 3032nd to 3051st, 3052nd to 3071st, At least 15 consecutive bases in the target region of the group consisting of positions 3168 to 3187, 3232 to 3270, 3302 to 3343, 3408 to 3427, 3590 to 3728, 3739 to 3764, 3877 to 3896, 3949 to 4030 and 4177 to 4225.

(6)根据(5)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第398位～第417位、第399位～第418位、第400位～第419位、第401位～第420位、第402位～第421位、第403位～第422位、第404位～第423位、第405位～第424位、第406位～第425位、第407位～第426位、第408位～第427位、第723位～第742位、第747位～第766位、第1148位～第1167位、第1289位～第1308位、第1484位～第1503位、第1488位～第1507位、第1491位～第1510位、第1493位～第1512位、第1506位～第1525位、第1517位～第1536位、第1531位～第1550位、第1545位～第1564位、第1578位～第1597位、第1579位～第1598位、第1580位～第1599位、第1581位～第1600位、第1582位～第1601位、第1583位～第1602位、第1584位～第1603位、第1585位～第1604位、第1586位～第1605位、第1587位～第1606位、第1588位～第1607位、第1589位～第1608位、第1590位～第1609位、第1591位～第1610位、第1592位～第1611位、第1593位～第1612位、第1594位～第1613位、第1595位～第1614位、第1596位～第1615位、第1597位～第1616位、第1598位～第1617位、第1599位～第1618位、第1600位～第1619位、第1601位～第1620位、第1602位～第1621位、第1603位～第1622位、第1604位～第1623位、第1605位～第1624位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1877位～第1896位、第1878位～第1897位、第1879位～第1898位、第1880位～第1899位、第1881位～第1900位、第1882位～第1901位、第1883位～第1902位、第1884位～第1903位、第1885位～第1904位、第1886位～第1905位、第1887位～第1906位、第2093位～第2112位、第2094位～第2113位、第2151位～第2170位、第2206位～第2225位、第2239位～第2258位、第2253位～第2272位、第2287位～第2306位、第2301位～第2320位、第2317位～第2336位、第2337位～第2356位、第2354位～第2373位、第2387位～第2406位、第2613位～第2632位、第2614位～第2633位、第2615位～第2634位、第2616位～第2635位、第2617位～第2636位、第2618位～第2637位、第2619位～第2638位、第2620位～第2639位、第2621位～第2640位、第2622位～第2641位、第2623位～第2642位、第2624位～第2643位、第2625位～第2644位、第2626位～第2645位、第2627位～第2646位、第2628位～第2647位、第2629位～第2648位、第2630位～第2649位、第2631位～第2650位、第2632位～第2651位、第2633位～第2652位、第2634位～第2653位、第2635位～第2654位、第2636位～第2655位、第2637位～第2656位、第2638位～第2657位、第2639位～第2658位、第2640位～第2659位、第2641位～第2660位、第2642位～第2661位、第2643位～第2662位、第2644位～第2663位、第2645位～第2664位、第2646位～第2665位、第2647位～第2666位、第2648位～第2667位、第2649位～第2668位、第2663位～第2682位、第2672位～第2691位、第2673位～第2692位、第2674位～第2693位、第2675位～第2694位、第2676位～第2695位、第2677位～第2696位、第2678位～第2697位、第2679位～第2698位、第2680位～第2699位、第2681位～第2700位、第2682位～第2701位、第2683位～第2702位、第2684位～第2703位、第2685位～第2704位、第2686位～第2705位、第2687位～第2706位、第2688位～第2707位、第2689位～第2708位、第2690位～第2709位、第2691位～第2710位、第2692位～第2711位、第2693位～第2712位、第2694位～第2713位、第2695位～第2714位、第2696位～第2715位、第2697位～第2716位、第2698位～第2717位、第2699位～第2718位、第2700位～第2719位、第2701位～第2720位、第2702位～第2721位、第2703位～第2722位、第2704位～第2723位、第2705位～第2724位、第2706位～第2725位、第2707位～第2726位、第2708位～第2727位、第2709位～第2728位、第2710位～第2729位、第2711位～第2730位、第2712位～第2731位、第2713位～第2732位、第2714位～第2733位、第2715位～第2734位、第2716位～第2735位、第2717位～第2736位、第2718位～第2737位、第2719位～第2738位、第2720位～第2739位、第2721位～第2740位、第2722位～第2741位、第2723位～第2742位、第2724位～第2743位、第2725位～第2744位、第2726位～第2745位、第2727位～第2746位、第2728位～第2747位、第2729位～第2748位、第2730位～第2749位、第2731位～第2750位、第2732位～第2751位、第2733位～第2752位、第2775位～第2794位、第2790位～第2809位、第2826位～第2845位、第2827位～第2846位、第2828位～第2847位、第2829位～第2848位、第2830位～第2849位、第2831位～第2850位、第2832位～第2851位、第2833位～第2852位、第2834位～第2853位、第2835位～第2854位、第2836位～第2855位、第2837位～第2856位、第2838位～第2857位、第2839位～第2858位、第2840位～第2859位、第2841位～第2860位、第2842位～第2861位、第2843位～第2862位、第2844位～第2863位、第2962位～第2981位、第2963位～第2982位、第3032位～第3051位、第3052位～第3071位、第3168位～第3187位、第3232位～第3251位、第3251位～第3270位、第3302位～第3321位、第3303位～第3322位、第3304位～第3323位、第3305位～第3324位、第3306位～第3325位、第3307位～第3326位、第3308位～第3327位、第3309位～第3328位、第3310位～第3329位、第3311位～第3330位、第3312位～第3331位、第3313位～第3332位、第3314位～第3333位、第3315位～第3334位、第3316位～第3335位、第3317位～第3336位、第3318位～第3337位、第3319位～第3338位、第3320位～第3339位、第3321位～第3340位、第3322位～第3341位、第3323位～第3342位、第3324位～第3343位、第3408位～第3427位、第3590位～第3609位、第3608位～第3627位、第3617位～第3636位、第3618位～第3637位、第3619位～第3638位、第3620位～第3639位、第3621位～第3640位、第3622位～第3641位、第3623位～第3642位、第3624位～第3643位、第3625位～第3644位、第3626位～第3645位、第3627位～第3646位、第3628位～第3647位、第3629位～第3648位、第3630位～第3649位、第3631位～第3650位、第3632位～第3651位、第3633位～第3652位、第3634位～第3653位、第3635位～第3654位、第3636位～第3655位、第3637位～第3656位、第3638位～第3657位、第3639位～第3658位、第3640位～第3659位、第3641位～第3660位、第3642位～第3661位、第3643位～第3662位、第3644位～第3663位、第3645位～第3664位、第3646位～第3665位、第3647位～第3666位、第3648位～第3667位、第3649位～第3668位、第3650位～第3669位、第3651位～第3670位、第3652位～第3671位、第3653位～第3672位、第3654位～第3673位、第3671位～第3690位、第3672位～第3691位、第3673位～第3692位、第3674位～第3693位、第3675位～第3694位、第3676位～第3695位、第3677位～第3696位、第3678位～第3697位、第3679位～第3698位、第3680位～第3699位、第3681位～第3700位、第3682位～第3701位、第3683位～第3702位、第3684位～第3703位、第3685位～第3704位、第3686位～第3705位、第3687位～第3706位、第3688位～第3707位、第3689位～第3708位、第3690位～第3709位、第3691位～第3710位、第3692位～第3711位、第3693位～第3712位、第3694位～第3713位、第3695位～第3714位、第3696位～第3715位、第3697位～第3716位、第3698位～第3717位、第3699位～第3718位、第3700位～第3719位、第3701位～第3720位、第3702位～第3721位、第3703位～第3722位、第3704位～第3723位、第3705位～第3724位、第3706位～第3725位、第3707位～第3726位、第3708位～第3727位、第3709位～第3728位、第3739位～第3758位、第3740位～第3759位、第3741位～第3760位、第3742位～第3761位、第3743位～第3762位、第3744位～第3763位、第3745位～第3764位、第3877位～第3896位、第3949位～第3968位、第3964位～第3983位、第3965位～第3984位、第3966位～第3985位、第3967位～第3986位、第3968位～第3987位、第3969位～第3988位、第3970位～第3989位、第3971位～第3990位、第3972位～第3991位、第3973位～第3992位、第3974位～第3993位、第3975位～第3994位、第3976位～第3995位、第3977位～第3996位、第3978位～第3997位、第3979位～第3998位、第3980位～第3999位、第3981位～第4000位、第3982位～第4001位、第3983位～第4002位、第3984位～第4003位、第3985位～第4004位、第3986位～第4005位、第3987位～第4006位、第3988位～第4007位、第3989位～第4008位、第3990位～第4009位、第3991位～第4010位、第3992位～第4011位、第3993位～第4012位、第3994位～第4013位、第3995位～第4014位、第3996位～第4015位、第3997位～第4016位、第3998位～第4017位、第3999位～第4018位、第4011位～第4030位、第4177位～第4196位、第4178位～第4197位、第4179位～第4198位、第4180位～第4199位、第4181位～第4200位、第4182位～第4201位、第4183位～第4202位、第4184位～第4203位、第4185位～第4204位、第4186位～第4205位、第4187位～第4206位、第4188位～第4207位、第4189位～第4208位、第4190位～第4209位、第4191位～第4210位、第4192位～第4211位、第4193位～第4212位、第4194位～第4213位、第4195位～第4214位、第4196位～第4215位、第4197位～第4216位、第4198位～第4217位、第4199位～第4218位、第4200位～第4219位、第4201位～第4220位、第4202位～第4221位、第4203位～第4222位、第4204位～第4223位、第4205位～第4224位和第4206位～第4225位组成的组中的靶区域中的至少15个连续的碱基。(6) The antisense oligonucleotide according to (5), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 14 to 33, 34 to 53, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 422, 404 to 423, 405th to 424th, 406th to 425th, 407th to 426th, 408th to 427th, 723rd to 742nd, 747th to 766th, 1148th to 1167th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 1510th, 1493rd to 1512th, 1506th to 1525th, 1517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1579th to 1598th, 1580th to 1599th, 1581st to 1600th, 1582nd to 1601st, 1583rd to 1602nd, 1584th to 1603rd, 1585th to 1604th, 1586th to 1605th, 1587th to 1606th 7th to 1606th, 1588th to 1607th, 1589th to 1608th, 1590th to 1609th, 1591st to 1610th, 1592nd to 1611th, 1593rd to 1612th, 1594th to 1613th, 1595th to 1614th, 1596th to 1615th, 1597th to 1616th, 1598th to 1617th, 1599th to 1618th, 1600th to 1619th, 1601st to 1620th, 1602nd to 1621st, 1603rd to 1622nd, 1604th to 1623rd, 1605th to 1624th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1896th, 1878th to 18 97th, 1879th to 1898th, 1880th to 1899th, 1881st to 1900th, 1882nd to 1901st, 1883rd to 1902nd, 1884th to 1903rd, 1885th to 1904th, 1886th to 1905th, 1887th to 1906th, 2093rd to 2112th, 2094th to 2113th, 2151st to 2170th , 2206th to 2225th, 2239th to 2258th, 2253rd to 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th to 2336th, 2337th to 2356th, 2354th to 2373rd, 2387th to 2406th, 2613th to 2632nd, 2614th to 2633rd, 2615th to 2634th, 2 616th to 2635th, 2617th to 2636th, 2618th to 2637th, 2619th to 2638th, 2620th to 2639th, 2621st to 2640th, 2622nd to 2641st, 2623rd to 2642nd, 2624th to 2643rd, 2625th to 2644th, 2626th to 2645th, 2627th to 2646th, 2628th 2640th to 2647th, 2641st to 2649th, 2642nd to 2641st, 2643rd to 2642nd, 2644th to 2643rd, 2645th to 2644th, 2646th to 2645th, 2647th to 2646th, 2648th to 2647th, 2649th to 2658th, 2640th to 2659th 2659th, 2641st to 2660th, 2642nd to 2661st, 2643rd to 2662nd, 2644th to 2663rd, 2645th to 2664th, 2646th to 2665th, 2647th to 2666th, 2648th to 2667th, 2649th to 2668th, 2663rd to 2682nd, 2672nd to 2691st, 2673rd to 2694th 2nd, 2674th to 2693rd, 2675th to 2694th, 2676th to 2695th, 2677th to 2696th, 2678th to 2697th, 2679th to 2698th, 2680th to 2699th, 2681st to 2700th, 2682nd to 2701st, 2683rd to 2702nd, 2684th to 2703rd, 2685th to 2704th, 2686th to 2705th, 2687th to 2706th, 2688th to 2707th, 2689th to 2708th, 2690th to 2709th, 2691st to 2710th, 2692nd to 2711th, 2693rd to 2712th, 2694th to 2713th, 2695th to 2714th, 2696th to 2715th, 2697th to 2716th, 2698th to 2717th 98th to 2717th, 2699th to 2718th, 2700th to 2719th, 2701st to 2720th, 2702nd to 2721st, 2703rd to 2722nd, 2704th to 2723rd, 2705th to 2724th, 2706th to 2725th, 2707th to 2726th, 2708th to 2727th, 2709th to 2728th, 2710th 2720-2739, 2721-2740, 2722-2741, 2723-2742, 2724-2743, 2725-2744, 2726-2745, 2727-2746, 2728-2747, 2729-2750, 2730-2731, 2732-2733, 2734-2735, 2736-2736, 2738-2737, 2739-2740, 2741-2741, 2742-2743 741st, 2723rd to 2742nd, 2724th to 2743rd, 2725th to 2744th, 2726th to 2745th, 2727th to 2746th, 2728th to 2747th, 2729th to 2748th, 2730th to 2749th, 2731st to 2750th, 2732nd to 2751st, 2733rd to 2752nd, 2775th to 2794th 2790th to 2809th, 2826th to 2845th, 2827th to 2846th, 2828th to 2847th, 2829th to 2848th, 2830th to 2849th, 2831st to 2850th, 2832nd to 2851st, 2833rd to 2852nd, 2834th to 2853rd, 2835th to 2854th, 2836th to 2855th, 2837th to 2856th, 2838th to 2857th, 2839th to 2858th, 2840th to 2859th, 2841st to 2860th, 2842nd to 2861st, 2843rd to 2862nd, 2844th to 2863rd, 2962nd to 2981st, 2963rd to 2982nd, 3032nd to 3051st, 3052nd to 3071st, 316th 8th to 3187th, 3232nd to 3251st, 3251st to 3270th, 3302nd to 3321st, 3303rd to 3322nd, 3304th to 3323rd, 3305th to 3324th, 3306th to 3325th, 3307th to 3326th, 3308th to 3327th, 3309th to 3328th, 3310th to 3329th, 3311th to 3330th, 3312th-3331st, 3313th-3332nd, 3314th-3333rd, 3315th-3334th, 3316th-3335th, 3317th-3336th, 3318th-3337th, 3319th-3338th, 3320th-3329th, 3321st-3340th, 3322nd-3341st, 3323rd-3344th 42nd, 3324th to 3343rd, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3618th to 3637th, 3619th to 3638th, 3620th to 3639th, 3621st to 3640th, 3622nd to 3641st, 3623rd to 3642nd, 3624th to 3643rd , 3625th to 3644th, 3626th to 3645th, 3627th to 3646th, 3628th to 3647th, 3629th to 3648th, 3630th to 3649th, 3631st to 3650th, 3632nd to 3651st, 3633rd to 3652nd, 3634th to 3653rd, 3635th to 3654th, 3636th to 3655th, 3 637th to 3656th, 3638th to 3657th, 3639th to 3658th, 3640th to 3659th, 3641st to 3660th, 3642nd to 3661st, 3643rd to 3662nd, 3644th to 3663rd, 3645th to 3664th, 3646th to 3665th, 3647th to 3666th, 3648th to 3667th, 3649th 3668th, 3650th - 3669th, 3651st - 3670th, 3652nd - 3671st, 3653rd - 3672nd, 3654th - 3673rd, 3671st - 3690th, 3672nd - 3691st, 3673rd - 3692nd, 3674th - 3693rd, 3675th - 3694th, 3676th - 3695th, 3677th - 3696th, 3678th to 3697th, 3679th to 3698th, 3680th to 3699th, 3681st to 3700th, 3682nd to 3701st, 3683rd to 3702nd, 3684th to 3703rd, 3685th to 3704th, 3686th to 3705th, 3687th to 3706th, 3688th to 3707th, 3689th to 3700th 8th, 3690th to 3709th, 3691st to 3710th, 3692nd to 3711th, 3693rd to 3712th, 3694th to 3713th, 3695th to 3714th, 3696th to 3715th, 3697th to 3716th, 3698th to 3717th, 3699th to 3718th, 3700th to 3719th, 3701st to 3720th, 3702nd to 3721st, 3703rd to 3722nd, 3704th to 3723rd, 3705th to 3724th, 3706th to 3725th, 3707th to 3726th, 3708th to 3727th, 3709th to 3728th, 3739th to 3758th, 3740th to 3759th, 3741st to 3760th, 3742nd to 3761st, 37 43rd to 3762nd, 3744th to 3763rd, 3745th to 3764th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3965th to 3984th, 3966th to 3985th, 3967th to 3986th, 3968th to 3987th, 3969th to 3988th, 3970th to 3989th, 3971st 3972nd to 3991st, 3973rd to 3992nd, 3974th to 3993rd, 3975th to 3994th, 3976th to 3995th, 3977th to 3996th, 3978th to 3997th, 3979th to 3998th, 3980th to 3999th, 3981st to 4000th, 3982nd to 4001st, 3983rd to 4004th 002, 3984th to 4003rd, 3985th to 4004th, 3986th to 4005th, 3987th to 4006th, 3988th to 4007th, 3989th to 4008th, 3990th to 4009th, 3991st to 4010th, 3992nd to 4011th, 3993rd to 4012th, 3994th to 4013th, 3995th to 4014th 3996th to 4015th, 3997th to 4016th, 3998th to 4017th, 3999th to 4018th, 4011th to 4030th, 4177th to 4196th, 4178th to 4197th, 4179th to 4198th, 4180th to 4199th, 4181st to 4200th, 4182nd to 4201st, 4183rd to 4202nd, 4184th to 4203rd, 4185th to 4204th, 4186th to 4205th, 4187th to 4206th, 4188th to 4207th, 4189th to 4208th, 4190th to 4209th, 4191st to 4210th, 4192nd to 4211th, 4193rd to 4212th, 4194th to 4213th, 4195th to 4214th, 4196th to 4215th At least 15 consecutive bases in the target region in the group consisting of positions 6 to 4215, 4197 to 4216, 4198 to 4217, 4199 to 4218, 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224 and 4206 to 4225.

(7)根据(3)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第54位～第73位、第148位～第167位、第397位～第432位、第747位～第778位、第965位～第984位、第1127位～第1146位、第1148位～第1173位、第1182位～第1213位、第1228位～第1254位、第1270位～第1308位、第1484位～第1564位、第1578位～第1629位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1870位～第1913位、第2015位～第2034位、第2086位～第2118位、第2129位～第2148位、第2151位～第2170位、第2206位～第2225位、第2239位～第2272位、第2287位～第2336位、第2337位～第2373位、第2387位～第2406位、第2598位～第2632位、第2633位～第2668位、第2672位～第2691位、第2699位～第2757位、第2775位～第2809位、第2826位～第2866位、第2959位～第2978位、第3032位～第3051位、第3052位～第3071位、第3136位～第3155位、第3168位～第3187位、第3188位～第3207位、第3232位～第3270位、第3298位～第3317位、第3325位～第3344位、第3408位～第3427位、第3590位～第3690位、第3691位～第3728位、第3739位～第3769位、第3877位～第3896位、第3949位～第3983位、第3984位～第4030位和第4170位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(7) The antisense oligonucleotide according to (3), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 432, 747 to 778, 965 to 984, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1228 to 1264, 1276 to 1283, 1291 to 1307, 1310 to 1329, 1331 to 1343, 1350 to 1361, 1371 to 1383, 1390 to 1411, 1401 to 1433, 1412 to 1443, 1423 to 1454, 1435 to 1464, 1445 to 1473, 1457 to 1483, 1491 to 1511 1254th, 1270th to 1308th, 1484th to 1564th, 1578th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1913th, 2015th to 2034th, 2086th to 2118th, 2129th to 2148th, 2151st to 2170th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2598th to 2632nd, 2633rd to 2668th, 2672nd to 2691st, 2699th to 2757th, 2775th to 2809th, 2826th to 2866th, 2959th to 2978th, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3155th, 3168th to At least 15 consecutive bases in the target region in the group consisting of positions 3187, 3188 to 3207, 3232 to 3270, 3298 to 3317, 3325 to 3344, 3408 to 3427, 3590 to 3690, 3691 to 3728, 3739 to 3769, 3877 to 3896, 3949 to 3983, 3984 to 4030 and 4170 to 4198.

(8)根据(7)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第54位～第73位、第148位～第167位、第397位～第416位、第413位～第432位、第747位～第766位、第756位～第775位、第759位～第778位、第965位～第984位、第1127位～第1146位、第1148位～第1167位、第1151位～第1170位、第1154位～第1173位、第1182位～第1201位、第1185位～第1204位、第1188位～第1207位、第1191位～第1210位、第1194位～第1213位、第1228位～第1247位、第1231位～第1250位、第1235位～第1254位、第1270位～第1289位、第1289位～第1308位、第1484位～第1503位、第1488位～第1507位、第1491位～第1510位、第1493位～第1512位、第1506位～第1525位、第1517位～第1536位、第1531位～第1550位、第1545位～第1564位、第1578位～第1597位、第1586位～第1605位、第1589位～第1608位、第1592位～第1611位、第1595位～第1614位、第1598位～第1617位、第1601位～第1620位、第1604位～第1623位、第1607位～第1626位、第1610位～第1629位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1870位～第1889位、第1871位～第1890位、第1874位～第1893位、第1877位～第1896位、第1880位～第1899位、第1883位～第1902位、第1886位～第1905位、第1889位～第1908位、第1894位～第1913位、第2015位～第2034位、第2086位～第2105位、第2097位～第2116位、第2099位～第2118位、第2129位～第2148位、第2151位～第2170位、第2206位～第2225位、第2239位～第2258位、第2253位～第2272位、第2287位～第2306位、第2301位～第2320位、第2317位～第2336位、第2337位～第2356位、第2354位～第2373位、第2387位～第2406位、第2598位～第2617位、第2613位～第2632位、第2633位～第2652位、第2649位～第2668位、第2672位～第2691位、第2699位～第2718位、第2702位～第2721位、第2705位～第2724位、第2708位～第2727位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2720位～第2739位、第2723位～第2742位、第2726位～第2745位、第2729位～第2748位、第2738位～第2757位、第2775位～第2794位、第2790位～第2809位、第2826位～第2845位、第2829位～第2848位、第2832位～第2851位、第2835位～第2854位、第2838位～第2857位、第2841位～第2860位、第2847位～第2866位、第2959位～第2978位、第3032位～第3051位、第3052位～第3071位、第3136位～第3155位、第3168位～第3187位、第3188位～第3207位、第3232位～第3251位、第3251位～第3270位、第3298位～第3317位、第3325位～第3344位、第3408位～第3427位、第3590位～第3609位、第3608位～第3627位、第3617位～第3636位、第3635位～第3654位、第3654位～第3673位、第3671位～第3690位、第3691位～第3710位、第3709位～第3728位、第3739位～第3758位、第3750位～第3769位、第3877位～第3896位、第3949位～第3968位、第3964位～第3983位、第3984位～第4003位、第3999位～第4018位、第4011位～第4030位、第4170位～第4189位、第4173位～第4192位、第4176位～第4195位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(8) The antisense oligonucleotide according to (7), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 416, 413 to 432, 747 to 766, 756 to 775, 759 to 778, 965 to 984, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1176 of the base sequence of SEQ ID NO: 471. 1173rd, 1182nd to 1201st, 1185th to 1204th, 1188th to 1207th, 1191st to 1210th, 1194th to 1213th, 1228th to 1247th, 1231st to 1250th, 1235th to 1254th, 1270th to 1289th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 1510th, 1493rd to 1512th, 1506th to 1525th, 1517th to 1536th , 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1586th to 1605th, 1589th to 1608th, 1592nd to 1611th, 1595th to 1614th, 1598th to 1617th, 1601st to 1620th, 1604th to 1623rd, 1607th to 1626th, 1610th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th 1890th - 1871st, 1890th - 1874th - 1893rd, 1897th - 1896th, 1880th - 1899th, 1883rd - 1902nd, 1886th - 1905th, 1889th - 1908th, 1894th - 1913th, 2015th - 2034th, 2086th - 2105th, 2097th - 2116th, 2099th - 2118th, 2129th - 2148th, 2151st - 2170th, 2206th - 2225th, 2239th - 225 8th, 2253rd to 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th to 2336th, 2337th to 2356th, 2354th to 2373rd, 2387th to 2406th, 2598th to 2617th, 2613th to 2632nd, 2633th to 2652nd, 2649th to 2668th, 2672nd to 2691st, 2699th to 2718th, 2702nd to 2721st, 2705th to 2724th, 2708th to 2727th, 27 11th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2723rd to 2742nd, 2726th to 2745th, 2729th to 2748th, 2738th to 2757th, 2775th to 2794th, 2790th to 2809th, 2826th to 2845th, 2829th to 2848th, 2832nd to 2851st, 2835th to 2854th, 2838th to 2857th, 2841st to 2860th, 2847th to 2869th 866th, 2959th to 2978th, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3155th, 3168th to 3187th, 3188th to 3207th, 3232nd to 3251st, 3251st to 3270th, 3298th to 3317th, 3325th to 3344th, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3635th to 3654th, 3654th to 3673rd, At least 15 consecutive bases in the target region in the group consisting of positions 3671 to 3690, 3691 to 3710, 3709 to 3728, 3739 to 3758, 3750 to 3769, 3877 to 3896, 3949 to 3968, 3964 to 3983, 3984 to 4003, 3999 to 4018, 4011 to 4030, 4170 to 4189, 4173 to 4192, 4176 to 4195 and 4179 to 4198.

(9)根据(5)或(7)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第747位～第766位、第1148位～第1167位、第1289位～第1308位、第1484位～第1564位、第1578位～第1623位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1877位～第1905位、第2151位～第2170位、第2206位～第2225位、第2239位～第2272位、第2287位～第2336位、第2337位～第2373位、第2387位～第2406位、第2613位～第2632位、第2633位～第2668位、第2672位～第2691位、第2699位～第2748位、第2775位～第2809位、第2826位～第2860位、第3032位～第3051位、第3052位～第3071位、第3168位～第3187位、第3232位～第3270位、第3408位～第3427位、第3590位～第3690位、第3691位～第3728位、第3739位～第3758位、第3877位～第3896位、第3949位～第3983位、第3984位～第4030位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(9) The antisense oligonucleotide according to (5) or (7), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: a base sequence selected from the 14th to 33rd, 34th to 53rd, 747th to 766th, 1148th to 1167th, 1289th to 1308th, 1484th to 1564th, and the 15th to 16th of the base sequence of SEQ ID NO: 471. 1578th to 1623rd, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1905th, 2151st to 2170th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2613th to 2632nd, 2633th to 2668th, 2672nd to 2691st, 2699th to 2748th, 2775th to 2809th, 2826th to 2860th, 3032nd to 3051st, 3052nd to 3071st, 3168th to 3187th, At least 15 consecutive bases in the target region in the group consisting of positions 3232 to 3270, 3408 to 3427, 3590 to 3690, 3691 to 3728, 3739 to 3758, 3877 to 3896, 3949 to 3983, 3984 to 4030 and 4179 to 4198.

(10-1)根据(9)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第747位～第766位、第1148位～第1167位、第1289位～第1308位、第1484位～第1503位、第1488位～第1507位、第1491位～第1510位、第1493位～第1512位、第1506位～第1525位、第1517位～第1536位、第1531位～第1550位、第1545位～第1564位、第1578位～第1597位、第1586位～第1605位、第1589位～第1608位、第1592位～第1611位、第1595位～第1614位、第1598位～第1617位、第1601位～第1620位、第1604位～第1623位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1877位～第1896位、第1880位～第1899位、第1883位～第1902位、第1886位～第1905位、第2151位～第2170位、第2206位～第2225位、第2239位～第2258位、第2253位～第2272位、第2287位～第2306位、第2301位～第2320位、第2317位～第2336位、第2337位～第2356位、第2354位～第2373位、第2387位～第2406位、第2613位～第2632位、第2633位～第2652位、第2649位～第2668位、第2672位～第2691位、第2699位～第2718位、第2702位～第2721位、第2705位～第2724位、第2708位～第2727位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2720位～第2739位、第2723位～第2742位、第2726位～第2745位、第2729位～第2748位、第2775位～第2794位、第2790位～第2809位、第2826位～第2845位、第2829位～第2848位、第2832位～第2851位、第2835位～第2854位、第2838位～第2857位、第2841位～第2860位、第3032位～第3051位、第3052位～第3071位、第3168位～第3187位、第3232位～第3251位、第3251位～第3270位、第3408位～第3427位、第3590位～第3609位、第3608位～第3627位、第3617位～第3636位、第3635位～第3654位、第3654位～第3673位、第3671位～第3690位、第3691位～第3710位、第3709位～第3728位、第3739位～第3758位、第3877位～第3896位、第3949位～第3968位、第3964位～第3983位、第3984位～第4003位、第3999位～第4018位、第4011位～第4030位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(10-1) The antisense oligonucleotide according to (9), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, wherein the nucleic acid comprises: a base sequence selected from positions 14 to 33, positions 34 to 53, positions 747 to 766, positions 1148 to 1167, positions 1289 to 1308, positions 1484 to 1503, positions 1488 to 1507 , 1491st to 1510th, 1493rd to 1512th, 1506th to 1525th, 1517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1586th to 1605th, 1589th to 1608th, 1592nd to 1611th, 1595th to 1614th, 1 598th to 1617th, 1601st to 1620th, 1604th to 1623rd, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1896th, 1880th to 1899th, 1883rd to 1902nd, 1886th to 1905th, 2151st 2170th - 2170th, 2206th - 2225th, 2239th - 2258th, 2253rd - 2272nd, 2287th - 2306th, 2301st - 2320th, 2317th - 2336th, 2337th - 2356th, 2354th - 2373rd, 2387th - 2406th, 2613th - 2632nd, 2633th - 2652nd, 2649th to 2668th, 2672nd to 2691st, 2699th to 2718th, 2702nd to 2721st, 2705th to 2724th, 2708th to 2727th, 2711th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2723rd to 274 2nd, 2726th to 2745th, 2729th to 2748th, 2775th to 2794th, 2790th to 2809th, 2826th to 2845th, 2829th to 2848th, 2832nd to 2851st, 2835th to 2854th, 2838th to 2857th, 2841st to 2860th, 3032nd to 3051st, 3052nd to 3071st, 3168th to 3187th, 3232nd to 3251st, 3251st to 3270th, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3635th to 3654th, 3654th to 3673rd, 3671st to 3690th, 36 At least 15 consecutive bases in the target region in the group consisting of positions 91 to 3710, 3709 to 3728, 3739 to 3758, 3877 to 3896, 3949 to 3968, 3964 to 3983, 3984 to 4003, 3999 to 4018, 4011 to 4030 and 4179 to 4198.

(10-2)根据(7)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第397位～第416位、第759位～第778位、第1127位～第1146位、第1148位～第1173位、第1182位～第1213位、第1488位～第1525位、第1586位～第1629位、第1686位～第1705位、第1768位～第1787位、第1870位～第1908位、第2097位～第2118位、第2151位～第2170位、第2239位～第2258位、第2287位～第2306位、第2317位～第2336位、第2633位～第2652位、第2702位～第2745位、第2832位～第2866位、第2959位～第2978位、第3298位～第3317位、第3635位～第3654位、第3671位～第3690位、第3691位～第3710位、第3750位～第3983位、第3984位～第4003位和第4170位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(10-2) The antisense oligonucleotide according to (7), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 397 to 416, 759 to 778, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1488 to 1525, 1586 to 1629, 1686 to 1705, 1768 to 1787, 1870 to 1908, 2097 to 2118, 2151 to 2167, 2170 to 2183, 2184 to 2191, 2213 to 2297, 2298 to 2299, 2301 to 2311, 2312 to 2323, 2330 to 2334, 2335 to 2348, 2350 to 2361, 2362 to 2371, 2373 to 2381, 2384 to 2391, 2391 to 2393, 2394 to 2397, 2398 to 2313, 2399 to 2314, 2315 to 2335 At least 15 consecutive bases in the target region selected from the group consisting of positions 2 to 2170, 2239 to 2258, 2287 to 2306, 2317 to 2336, 2633 to 2652, 2702 to 2745, 2832 to 2866, 2959 to 2978, 3298 to 3317, 3635 to 3654, 3671 to 3690, 3691 to 3710, 3750 to 3983, 3984 to 4003, and 4170 to 4198.

(10-3)根据(7)或(8)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第397位～第416位、第759位～第778位、第1127位～第1146位、第1148位～第1167位、第1151位～第1170位、第1154位～第1173位、第1182位～第1201位、第1185位～第1204位、第1194位～第1213位、第1488位～第1507位、第1491位～第1510位、第1506位～第1525位、第1586位～第1605位、第1589位～第1608位、第1595位～第1614位、第1598位～第1617位、第1601位～第1620位、第1604位～第1623位、第1607位～第1626位、第1610位～第1629位、第1686位～第1705位、第1768位～第1787位、第1870位～第1889位、第1871位～第1890位、第1874位～第1893位、第1877位～第1896位、第1886位～第1905位、第1889位～第1908位、第2097位～第2116位、第2099位～第2118位、第2151位～第2170位、第2239位～第2258位、第2287位～第2306位、第2317位～第2336位、第2633位～第2652位、第2702位～第2721位、第2705位～第2724位、第2708位～第2727位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2720位～第2739位、第2726位～第2745位、第2832位～第2851位、第2835位～第2854位、第2841位～第2860位、第2847位～第2866位、第2959位～第2978位、第3298位～第3317位、第3635位～第3654位、第3671位～第3690位、第3691位～第3710位、第3750位～第3769位、第3964位～第3983位、第3984位～第4003位、第4170位～第4189位、第4173位～第4192位、第4176位～第4195位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(10-3) The antisense oligonucleotide according to (7) or (8), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 397 to 416, 759 to 778, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1173, 1182 to 1201, 1185 to 1204, 1194 to 1213, 1488 to 1507, 1491 to 1510, 1506 to 1517 of the base sequence of SEQ ID NO: 471. 1525th, 1586th - 1605th, 1589th - 1608th, 1595th - 1614th, 1598th - 1617th, 1601st - 1620th, 1604th - 1623rd, 1607th - 1626th, 1610th - 1629th, 1686th - 1705th, 1768th - 1787th, 1870th - 1889th, 1871st - 1890th, 1874th - 1893rd, 1877th - 1896th, 1886th - 1905th, 1889th - 1904th 08, 2097th to 2116th, 2099th to 2118th, 2151st to 2170th, 2239th to 2258th, 2287th to 2306th, 2317th to 2336th, 2633rd to 2652nd, 2702nd to 2721st, 2705th to 2724th, 2708th to 2727th, 2711th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2726th to 2745th, 2832nd to 2851st, At least 15 consecutive bases in the target region in the group consisting of positions 2835 to 2854, 2841 to 2860, 2847 to 2866, 2959 to 2978, 3298 to 3317, 3635 to 3654, 3671 to 3690, 3691 to 3710, 3750 to 3769, 3964 to 3983, 3984 to 4003, 4170 to 4189, 4173 to 4192, 4176 to 4195 and 4179 to 4198.

(10-4)根据(7)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第397位～第416位、第1194位～第1213位、第1506位～第1525位、第1586位～第1626位、第1870位～第1896位、第2097位～第2116位、第2317位～第2336位、第2633位～第2652位、第2702位～第2739位、第2841位～第2978位、第3298位～第3317位、第3635位～第3654位、第3691位～第3710位、第3750位～第3769位、第3984位～第4003位和第4170位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(10-4) The antisense oligonucleotide according to (7), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 397 to 416, 1194 to 1213, 1506 to 1525, 1586 to 1626, 1870 to 1896, 2097 to 2116, and 231 At least 15 consecutive bases in the target region in the group consisting of positions 7 to 2336, positions 2633 to 2652, positions 2702 to 2739, positions 2841 to 2978, positions 3298 to 3317, positions 3635 to 3654, positions 3691 to 3710, positions 3750 to 3769, positions 3984 to 4003, and positions 4170 to 4198.

(10-5)根据(7)或(8)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第397位～第416位、第1194位～第1213位、第1506位～第1525位、第1586位～第1605位、第1595位～第1614位、第1598位～第1617位、第1604位～第1623位、第1607位～第1626位、第1870位～第1889位、第1871位～第1890位、第1874位～第1893位、第1877位～第1896位、第2097位～第2116位、第2317位～第2336位、第2633位～第2652位、第2702位～第2721位、第2708位～第2727位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2720位～第2739位、第2841位～第2860位、第2959位～第2978位、第3298位～第3317位、第3635位～第3654位、第3691位～第3710位、第3750位～第3769位、第3984位～第4003位、第4170位～第4189位、第4173位～第4192位、第4176位～第4195位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(10-5) The antisense oligonucleotide according to (7) or (8), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 397 to 416, 1194 to 1213, 1506 to 1525, 1586 to 1605, 1595 to 1614, 1598 to 1617, 1604 to 1623, 1607 to 1626, 1870 to 1889, 1871 to 1890, 1874 to 1893, 1877 to 1896, 2097 to 2116, 2317 to 2336, 2341 to 2357, 633rd to 2652nd, 2702nd to 2721st, 2708th to 2727th, 2711th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2841st to 2860th, 2959th to 2978th, 3298th to 331st At least 15 consecutive bases in the target region in the group consisting of positions 37, 3635-3654, 3691-3710, 3750-3769, 3984-4003, 4170-4189, 4173-4192, 4176-4195 and 4179-4198.

(11)根据(7)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1598位～第1626位、第1870位～第1890位、第2097位～第2116位、第2711位～第2736位、第2841位～第2860位和第4170位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(11) The antisense oligonucleotide according to (7) or its pharmaceutically acceptable salt or hydrate thereof, which is complementary to the following nucleic acid, wherein the nucleic acid comprises: at least 15 consecutive bases in a target region selected from the group consisting of positions 1598 to 1626, positions 1870 to 1890, positions 2097 to 2116, positions 2711 to 2736, positions 2841 to 2860 and positions 4170 to 4198 of the base sequence of sequence number 471.

(12)根据(7)或(8)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1598位～第1617位、第1604位～第1623位、第1607位～第1626位、第1870位～第1889位、第1871位～第1890位、第2097位～第2116位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2841位～第2860位、第4170位～第4189位、第4173位～第4192位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。(12) The antisense oligonucleotide according to (7) or (8), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 1598 to 1617, positions 1604 to 1623, positions 1607 to 1626, positions 1870 to 1889, positions 1871 to 1890, positions 2097 to 2116, positions 2711 to 2730, positions 2714 to 2733, positions 2717 to 2736, positions 2841 to 2860, positions 4170 to 4189, positions 4173 to 4192, and positions 4179 to 4198 of the base sequence of SEQ ID NO: 471.

(12’-1)根据(5)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第400位～第425位、第1581位～第1624位、第1878位～第1898位、第2094位～第2113位、第2629位～第2656位、第2700位～第2741位、第2839位～第2863位、第2962位～第2981位、第3302位～第3325位、第3631位～第3658位、第3687位～第3714位、第3745位～第3764位、第3980位～第4007位、第4177位～第4199位和第4204位～第4223位组成的组中的靶区域中的至少15个连续的碱基。(12'-1) The antisense oligonucleotide according to (5), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 400 to 425, positions 1581 to 1624, positions 1878 to 1898, positions 2094 to 2113, positions 2629 to 2656, positions 2700 to 2747 of the base sequence of SEQ ID NO: 471; At least 15 consecutive bases in the target region in the group consisting of position 1, position 2839 to position 2863, position 2962 to position 2981, position 3302 to position 3325, position 3631 to position 3658, position 3687 to position 3714, position 3745 to position 3764, position 3980 to position 4007, position 4177 to position 4199 and position 4204 to position 4223.

(12’-2)根据(5)或(6)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第400位～第419位、第403位～第422位、第406位～第425位、第1581位～第1600位、第1582位～第1601位、第1583位～第1602位、第1584位～第1603位、第1585位～第1604位、第1587位～第1606位、第1588位～第1607位、第1590位～第1609位、第1591位～第1610位、第1592位～第1611位、第1593位～第1612位、第1594位～第1613位、第1596位～第1615位、第1597位～第1616位、第1599位～第1618位、第1600位～第1619位、第1602位～第1621位、第1603位～第1622位、第1605位～第1624位、第1878位～第1897位、第1879位～第1898位、第2094位～第2113位、第2629位～第2648位、第2637位～第2656位、第2700位～第2719位、第2701位～第2720位、第2703位～第2722位、第2704位～第2723位、第2706位～第2725位、第2707位～第2726位、第2709位～第2728位、第2710位～第2729位、第2712位～第2731位、第2713位～第2732位、第2715位～第2734位、第2716位～第2735位、第2718位～第2737位、第2719位～第2738位、第2721位～第2740位、第2722位～第2741位、第2839位～第2858位、第2840位～第2859位、第2842位～第2861位、第2843位～第2862位、第2844位～第2863位、第2962位～第2981位、第3302位～第3321位、第3306位～第3325位、第3631位～第3650位、第3632位～第3651位、第3633位～第3652位、第3634位～第3653位、第3636位～第3655位、第3637位～第3656位、第3638位～第3657位、第3639位～第3658位、第3687位～第3706位、第3695位～第3714位、第3745位～第3764位、第3980位～第3999位、第3988位～第4007位、第4177位～第4196位、第4178位～第4197位、第4180位～第4199位和第4204位～第4223位组成的组中的靶区域中的至少15个连续的碱基。(12'-2) The antisense oligonucleotide according to (5) or (6), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 400 to 419, 403 to 422, 406 to 425, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1590 to 1609, 1591 to 1610, 1592 to 1611, 1593 to 1614, 612th, 1594th to 1613th, 1596th to 1615th, 1597th to 1616th, 1599th to 1618th, 1600th to 1619th, 1602nd to 1621st, 1603rd to 1622nd, 1605th to 1624th, 1878th to 1897th , 1879th to 1898th, 2094th to 2113th, 2629th to 2648th, 2637th to 2656th, 2700th to 2719th, 2701st to 2720th, 2703rd to 2722nd, 2704th to 2723rd, 2706th to 2725th, 270 7th to 2726th, 2709th to 2728th, 2710th to 2729th, 2712th to 2731st, 2713th to 2732nd, 2715th to 2734th, 2716th to 2735th, 2718th to 2737th, 2719th to 2738th, 2721st to 2740th, 2722nd to 2741st, 2839th to 2858th, 2840th to 2859th, 2842nd to 2861st, 2843rd to 2862nd, 2844th to 2863rd, 2962nd to 2981st, 3302nd to 3321st, 3306th to 3325th 3631st to 3650th, 3632nd to 3651st, 3633rd to 3652nd, 3634th to 3653rd, 3636th to 3655th, 3637th to 3656th, 3638th to 3657th, 3639th to 3658th, 3687th to 3706th, 3 At least 15 consecutive bases in the target region of the group consisting of positions 695 to 3714, 3745 to 3764, 3980 to 3999, 3988 to 4007, 4177 to 4196, 4178 to 4197, 4180 to 4199 and 4204 to 4223.

(12’-3)根据(5)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第400位～第425位、第1581位～第1624位、第1878位～第1898位、第2637位～第2656位、第2700位～第2741位、第2839位～第2863位、第2962位～第2981位、第3302位～第3325位、第3631位～第3658位、第3687位～第3706位、第3745位～第3764位、第4177位～第4199位和第4204位～第4223位组成的组中的靶区域中的至少15个连续的碱基。(12'-3) The antisense oligonucleotide according to (5) or its pharmaceutically acceptable salt or hydrate thereof, which is complementary to the following nucleic acid, wherein the nucleic acid comprises: at least 15 consecutive bases in the target region selected from the group consisting of positions 400 to 425, positions 1581 to 1624, positions 1878 to 1898, positions 2637 to 2656, positions 2700 to 2741, positions 2839 to 2863, positions 2962 to 2981, positions 3302 to 3325, positions 3631 to 3658, positions 3687 to 3706, positions 3745 to 3764, positions 4177 to 4199 and positions 4204 to 4223 of the base sequence of sequence number 471.

(12’-4)根据(5)或(6)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第400位～第419位、第403位～第422位、第406位～第425位、第1581位～第1600位、第1582位～第1601位、第1583位～第1602位、第1584位～第1603位、第1585位～第1604位、第1587位～第1606位、第1588位～第1607位、第1591位～第1610位、第1592位～第1611位、第1593位～第1612位、第1594位～第1613位、第1596位～第1615位、第1597位～第1616位、第1600位～第1619位、第1602位～第1621位、第1603位～第1622位、第1605位～第1624位、第1878位～第1897位、第1879位～第1898位、第2637位～第2656位、第2700位～第2719位、第2701位～第2720位、第2703位～第2722位、第2704位～第2723位、第2706位～第2725位、第2707位～第2726位、第2709位～第2728位、第2710位～第2729位、第2712位～第2731位、第2713位～第2732位、第2715位～第2734位、第2716位～第2735位、第2718位～第2737位、第2719位～第2738位、第2721位～第2740位、第2722位～第2741位、第2839位～第2858位、第2840位～第2859位、第2842位～第2861位、第2843位～第2862位、第2844位～第2863位、第2962位～第2981位、第3302位～第3321位、第3306位～第3325位、第3631位～第3650位、第3632位～第3651位、第3633位～第3652位、第3634位～第3653位、第3636位～第3655位、第3637位～第3656位、第3638位～第3657位、第3639位～第3658位、第3687位～第3706位、第3745位～第3764位、第4177位～第4196位、第4178位～第4197位、第4180位～第4199位和第4204位～第4223位组成的组中的靶区域中的至少15个连续的碱基。(12'-4) The antisense oligonucleotide according to (5) or (6), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 400 to 419, 403 to 422, 406 to 425, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1591 to 1610, 1592 to 1611 of the base sequence selected from the group consisting of: , 1593rd to 1612th, 1594th to 1613th, 1596th to 1615th, 1597th to 1616th, 1600th to 1619th, 1602nd to 1621st, 1603rd to 1622nd, 1605th to 1624th, 1878th to 1897th, 1879th to 1898th, 2637th to 2656th, 2700th to 2719th, 2701st to 2720th, 2703rd to 2722nd, 2704th to 2723rd, 2706th to 2725th, 2707th to 2726th 6th, 2709th to 2728th, 2710th to 2729th, 2712th to 2731st, 2713th to 2732nd, 2715th to 2734th, 2716th to 2735th, 2718th to 2737th, 2719th to 2738th, 2721st to 2740th, 2722nd to 2741st, 2839th to 2858th, 2840th to 2859th, 2842nd to 2861st, 2843rd to 2862nd, 2844th to 2863rd, 2962nd to 2981st, 3302nd to 3303rd 321, 3306-3325, 3631-3650, 3632-3651, 3633-3652, 3634-3653, 3636-3655, 3637-3656, 3638-3657, 3639-3658, 3687-3706, 3745-3764, 4177-4196, 4178-4197, 4180-4199 and 4204-4223. At least 15 consecutive bases in the target region.

(12’-5)根据(5)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1581位～第1624位、第2703位～第2740位、第3633位～第3655位和第4177位～第4199位组成的组中的靶区域中的至少15个连续的碱基。(12'-5) The antisense oligonucleotide according to (5) or its pharmaceutically acceptable salt or hydrate thereof, which is complementary to the following nucleic acid, wherein the nucleic acid comprises: at least 15 consecutive bases in the target region selected from the group consisting of positions 1581 to 1624, positions 2703 to 2740, positions 3633 to 3655 and positions 4177 to 4199 of the base sequence of sequence number 471.

(12’-6)根据(5)或(6)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1581位～第1600位、第1582位～第1601位、第1584位～第1603位、第1585位～第1604位、第1587位～第1606位、第1588位～第1607位、第1594位～第1613位、第1596位～第1615位、第1597位～第1616位、第1602位～第1621位、第1603位～第1622位、第1605位～第1624位、第2703位～第2722位、第2707位～第2726位、第2709位～第2728位、第2710位～第2729位、第2712位～第2731位、第2713位～第2732位、第2715位～第2734位、第2716位～第2735位、第2718位～第2737位、第2719位～第2738位、第2721位～第2740位、第3633位～第3652位、第3634位～第3653位、第3636位～第3655位、第4177位～第4196位、第4178位～第4197位和第4180位～第4199位组成的组中的靶区域中的至少15个连续的碱基。(12'-6) The antisense oligonucleotide according to (5) or (6), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to the following nucleic acid, the nucleic acid comprising: positions 1581 to 1600, 1582 to 1601, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1594 to 1613, 1596 to 1615, 1597 to 1616, 1602 to 1621, 1603 to 1622, 1605 to 1624, 2703 to 2706 of the base sequence of SEQ ID NO: 471. At least 15 consecutive bases in the target region in the group consisting of position 2722, position 2707 to position 2726, position 2709 to position 2728, position 2710 to position 2729, position 2712 to position 2731, position 2713 to position 2732, position 2715 to position 2734, position 2716 to position 2735, position 2718 to position 2737, position 2719 to position 2738, position 2721 to position 2740, position 3633 to position 3652, position 3634 to position 3653, position 3636 to position 3655, position 4177 to position 4196, position 4178 to position 4197 and position 4180 to position 4199.

(12’-7)根据(5)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1587位～第1616位、第2712位～第2735位和第4180位～第4199位组成的组中的靶区域中的至少15个连续的碱基。(12'-7) The antisense oligonucleotide according to (5) or its pharmaceutically acceptable salt or hydrate thereof, which is complementary to the following nucleic acid, wherein the nucleic acid comprises: at least 15 consecutive bases in a target region selected from the group consisting of positions 1587 to 1616, positions 2712 to 2735 and positions 4180 to 4199 of the base sequence of sequence number 471.

(12’-8)根据(5)或(6)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1587位～第1606位、第1597位～第1616位、第2712位～第2731位、第2716位～第2735位和第4180位～第4199位组成的组中的靶区域中的至少15个连续的碱基。(12'-8) The antisense oligonucleotide according to (5) or (6) or its pharmaceutically acceptable salt or hydrate thereof, which is complementary to the following nucleic acid, wherein the nucleic acid comprises: at least 15 consecutive bases in the target region selected from the group consisting of positions 1587 to 1606, positions 1597 to 1616, positions 2712 to 2731, positions 2716 to 2735 and positions 4180 to 4199 of the base sequence of sequence number 471.

(13)根据(1)～(12)中任一项所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其与包含上述靶区域的至少20个连续的碱基的核酸互补。(13) The antisense oligonucleotide according to any one of (1) to (12), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to a nucleic acid comprising at least 20 consecutive bases of the target region.

(14)根据(3)或(4)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(14) The antisense oligonucleotide according to (3) or (4), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号1～6、8、9、11、14～24、26、29、31～60、66～67、73～75、79～82、86～89、92～111、115～136、138～145、147～158和160～464组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464;

(ii)在选自由序列号1～6、8、9、11、14～24、26、29、31～60、66～67、73～75、79～82、86～89、92～111、115～136、138～145、147～158和160～464组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158 and 160 to 464; or

(iii)相对于选自由序列号1～6、8、9、11、14～24、26、29、31～60、66～67、73～75、79～82、86～89、92～111、115～136、138～145、147～158和160～464组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a base sequence having a sequence identity of 90% or more to a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464.

(15)根据(5)或(6)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(15) The antisense oligonucleotide according to (5) or (6), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号1、5、6、14～24、31～35、37～40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163～464组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14-24, 31-35, 37-40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158, and 163-464;

(ii)在选自由序列号1、5、6、14～24、31～35、37～40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163～464组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163 to 464; or

(iii)相对于选自由序列号1、5、6、14～24、31～35、37～40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163～464组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a base sequence having a sequence identity of 90% or more to a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163 to 464.

(16)根据(7)或(8)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(16) The antisense oligonucleotide according to (7) or (8), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号1～4、6、8、9、11、14～24、26、29、31～37、39～50、52～60、66～67、73～75、79～82、86～89、92～111、115～118、120～136、138～145、147～158和160～163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163;

(ii)在选自由序列号1～4、6、8、9、11、14～24、26、29、31～37、39～50、52～60、66～67、73～75、79～82、86～89、92～111、115～118、120～136、138～145、147～158和160～163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158 and 160 to 163; or

(iii)相对于选自由序列号1～4、6、8、9、11、14～24、26、29、31～37、39～50、52～60、66～67、73～75、79～82、86～89、92～111、115～118、120～136、138～145、147～158和160～163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a base sequence having a sequence identity of 90% or more to a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158 and 160 to 163.

(17-1)根据(9)或(10-1)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(17-1) The antisense oligonucleotide according to (9) or (10-1), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号1、6、14～24、31～35、37、39、40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14-24, 31-35, 37, 39, 40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158 and 163;

(ii)在选自由序列号1、6、14～24、31～35、37、39、40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163; or

(iii)相对于选自由序列号1、6、14～24、31～35、37、39、40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a base sequence having a sequence identity of 90% or more to a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163.

(17-2)根据(10-2)或(10-3)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(17-2) The antisense oligonucleotide according to (10-2) or (10-3), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号9、11、16、17、22、31、60、67、73、74、75、79、80、92、95～107、110、111、116、117、120～122、126、128～134、136、140、141、143～145、148、151～154、156、157和160～163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95-107, 110, 111, 116, 117, 120-122, 126, 128-134, 136, 140, 141, 143-145, 148, 151-154, 156, 157, and 160-163;

(ii)在选自由序列号9、11、16、17、22、31、60、67、73、74、75、79、80、92、95～107、110、111、116、117、120～122、126、128～134、136、140、141、143～145、148、151～154、156、157和160～163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157 and 160 to 163; or

(iii)相对于选自由序列号9、11、16、17、22、31、60、67、73、74、75、79、80、92、95～107、110、111、116、117、120～122、126、128～134、136、140、141、143～145、148、151～154、156、157和160～163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a base sequence having a sequence identity of 90% or more to a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157 and 160 to 163.

(17-3)根据(10-4)或(10-5)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(17-3) The antisense oligonucleotide according to (10-4) or (10-5), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号11、60、92、95、97、98、100、101、104～107、116、122、126、128、130～134、143、145、148、151、153、154、157和160～163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104-107, 116, 122, 126, 128, 130-134, 143, 145, 148, 151, 153, 154, 157, and 160-163;

(ii)在选自由序列号11、60、92、95、97、98、100、101、104～107、116、122、126、128、130～134、143、145、148、151、153、154、157和160～163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157 and 160 to 163; or

(iii)相对于选自由序列号11、60、92、95、97、98、100、101、104～107、116、122、126、128、130～134、143、145、148、151、153、154、157和160～163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a base sequence having a sequence identity of 90% or more to a base sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157 and 160 to 163.

(18)根据(11)或(12)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(18) The antisense oligonucleotide according to (11) or (12), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号98、100、101、104、105、116、131～133、143、160、161和163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131-133, 143, 160, 161 and 163;

(ii)在选自由序列号98、100、101、104、105、116、131～133、143、160、161和163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161 and 163; or

(iii)相对于选自由序列号98、100、101、104、105、116、131～133、143、160、161和163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161 and 163.

(19-1)根据(12’-1)或(12’-2)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(19-1) The antisense oligonucleotide according to (12'-1) or (12'-2), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号21、164～222、233、234和350～355组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355;

(ii)在选自由序列号21、164～222、233、234和350～355组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234 and 350 to 355; or

(iii)相对于选自由序列号21、164～222、233、234和350～355组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a nucleotide sequence having a sequence identity of 90% or more to the nucleotide sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355.

(19-2)根据(12’-3)或(12’-4)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(19-2) The antisense oligonucleotide according to (12'-3) or (12'-4), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号21、164～171、173～177、179～184、187～214、216、219～222、233～234和350～355组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355;

(ii)在选自由序列号21、164～171、173～177、179～184、187～214、216、219～222、233～234和350～355组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234 and 350 to 355; or

(iii)相对于选自由序列号21、164～171、173～177、179～184、187～214、216、219～222、233～234和350～355组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355.

(19-3)根据(12’-5)或(12’-6)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(19-3) The antisense oligonucleotide according to (12'-5) or (12'-6), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号167～171、175～177、180～182、190、193～202、219～221、233和351～353组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353;

(ii)在选自由序列号167～171、175～177、180～182、190、193～202、219～221、233和351～353组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233 and 351 to 353; or

(iii)相对于选自由序列号167～171、175～177、180～182、190、193～202、219～221、233和351～353组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353.

(20)根据(12’-7)或(12’-8)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(20) The antisense oligonucleotide according to (12'-7) or (12'-8), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号170、177、196、199和221组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199 and 221;

(ii)在选自由序列号170、177、196、199和221组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199 and 221; or

(iii)相对于选自由序列号170、177、196、199和221组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a nucleotide sequence having a sequence identity of 90% or more to the nucleotide sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199 and 221.

(21)根据(14)～(20)中任一项所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含(i)的碱基序列。(21) The antisense oligonucleotide according to any one of (14) to (20), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising the base sequence of (i).

(22)一种反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第468位～第487位、第474位～第493位、第583位～第602位、第586位～第605位、第619位～第638位、第770位～第789位、第774位～第793位、第775位～第794位、第778位～第797位、第804位～第823位、第851位～第870位、第1160位～第1179位、第1162位～第1181位、第1170位～第1189位、第1173位～第1192位、第1205位～第1224位、第1210位～第1229位、第1216位～第1235位、第1217位～第1236位、第1219位～第1238位、第1385位～第1404位、第1441位～第1460位、第1818位～第1837位、第1902位～第1921位、第1905位～第1924位、第1908位～第1927位、第1914位～第1933位、第1931位～第1950位、第2117位～第2136位、第2749位～第2768位、第3100位～第3119位和第4125位～第4144位组成的组中的靶区域中的至少15个连续的碱基。(22) An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof, which consists of 15 to 22 nucleotides and is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 468 to 487, 474 to 493, 583 to 602, 586 to 605, 619 to 638, 770 to 789, 774 to 793, 775 to 794, 778 to 797, 804 to 823, 851 to 870, 1160 to 1179, 1162 to 1181, 1170 to 1189, 1173 to 1192 of the base sequence of SEQ ID NO: 471. 1205th to 1224th, 1210th to 1229th, 1216th to 1235th, 1217th to 1236th, 1219th to 1238th, 1385th to 1404th, 1441st to 1460th, 1818th to 1837th, 1902nd to 1921st, 1 At least 15 consecutive bases in the target region of the group consisting of positions 905 to 1924, 1908 to 1927, 1914 to 1933, 1931 to 1950, 2117 to 2136, 2749 to 2768, 3100 to 3119 and 4125 to 4144.

(23)根据(22)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含：(23) The antisense oligonucleotide according to (22), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i)选自由序列号7、10、12、13、25、27、28、30、61～65、68～72、76～78、83～85、90、91、112～114、137、146和159组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61-65, 68-72, 76-78, 83-85, 90, 91, 112-114, 137, 146 and 159;

(ii)在选自由序列号7、10、12、13、25、27、28、30、61～65、68～72、76～78、83～85、90、91、112～114、137、146和159组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146 and 159; or

(iii)相对于选自由序列号7、10、12、13、25、27、28、30、61～65、68～72、76～78、83～85、90、91、112～114、137、146和159组成的组中的碱基序列具有90％以上的序列一致性的碱基序列。(iii) a base sequence having a sequence identity of 90% or more to a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146 and 159.

(24)根据(23)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其包含(i)的碱基序列。(24) The antisense oligonucleotide according to (23), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which comprises the base sequence of (i).

(25)根据(1)～(24)中任一项所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其中，反义寡核苷酸由20个核苷酸构成。(25) The antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof according to any one of (1) to (24), wherein the antisense oligonucleotide consists of 20 nucleotides.

(26)根据(1)～(25)中任一项所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其中，构成上述寡核苷酸的至少1个核苷酸的糖部分和/或磷酸键部分进行了修饰。(26) The antisense oligonucleotide according to any one of (1) to (25), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the sugar portion and/or the phosphate bond portion of at least one nucleotide constituting the oligonucleotide is modified.

(27-1)根据(26)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其中，反义寡核苷酸为包含中间的间隔区域以及与间隔区域的5’末端侧和3’末端侧相邻的2个侧翼区域(5’侧翼区域和3’侧翼区域)的间隔寡核苷酸(gapmer)。(27-1) The antisense oligonucleotide according to (26) or its pharmaceutically acceptable salt or hydrate thereof, wherein the antisense oligonucleotide is a gapmer comprising a middle spacer region and two flanking regions (5’ flanking region and 3’ flanking region) adjacent to the 5’ terminal side and the 3’ terminal side of the spacer region.

(27-2)根据(27-1)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其中，反义寡核苷酸从5’侧向3’侧由核苷酸长度为5的5’侧翼区域、核苷酸长度为10的间隔区域和核苷酸长度为5的3’侧翼区域构成。(27-2) The antisense oligonucleotide according to (27-1) or its pharmaceutically acceptable salt or hydrate thereof, wherein the antisense oligonucleotide is composed of a 5’ flanking region with a nucleotide length of 5, a spacer region with a nucleotide length of 10 and a 3’ flanking region with a nucleotide length of 5 from the 5’ side to the 3’ side.

(28)根据(27-1)或(27-2)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其中，核苷之间的键全部为硫代磷酸酯键。(28) The antisense oligonucleotide according to (27-1) or (27-2), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein all the bonds between nucleosides are phosphorothioate bonds.

(29)根据(27-1)或(27-2)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其中，从5’侧翼区域的5’侧起的第2位与第3位的核苷之间的键、第3位与第4位的核苷之间的键和第4位与第5位的核苷之间的键中的一个以上为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第1位与第2位的核苷之间的键、第2位与第3位的核苷之间的键和第3位与第4位的核苷之间的键中的一个以上为磷酸二酯键，(29) The antisense oligonucleotide according to (27-1) or (27-2), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein at least one of the bonds between the 2nd and 3rd nucleosides, the bonds between the 3rd and 4th nucleosides, and the bonds between the 4th and 5th nucleosides from the 5' side of the 5' flanking region is a phosphodiester bond, and/or at least one of the bonds between the 1st and 2nd nucleosides, the bonds between the 2nd and 3rd nucleosides, and the bonds between the 3rd and 4th nucleosides from the 5' side of the 3' flanking region is a phosphodiester bond,

并且其它核苷之间的键全部为硫代磷酸酯键。And the bonds between other nucleosides are all phosphorothioate bonds.

(30)根据(29)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其中，从5’侧翼区域的5’侧起的第2位与第3位的核苷之间的键和第4位与第5位的核苷之间的键为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第1位与第2位的核苷之间的键和第3位与第4位的核苷之间的键为磷酸二酯键，(30) The antisense oligonucleotide according to (29), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the bond between the 2nd and 3rd nucleosides and the bond between the 4th and 5th nucleosides from the 5' side of the 5' flanking region are phosphodiester bonds, and/or the bond between the 1st and 2nd nucleosides and the bond between the 3rd and 4th nucleosides from the 5' side of the 3' flanking region are phosphodiester bonds,

并且其它核苷之间的键全部为硫代磷酸酯键。And the bonds between other nucleosides are all phosphorothioate bonds.

(31)根据(29)所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其中，从5’侧翼区域的5’侧起的第2位与第3位的核苷之间的键、第3位与第4位的核苷之间的键和第4位与第5位的核苷之间的键为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第1位与第2位的核苷之间的键、第2位与第3位的核苷之间的键和第3位与第4位的核苷之间的键为磷酸二酯键，(31) The antisense oligonucleotide according to (29), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the bond between the 2nd and 3rd nucleosides, the bond between the 3rd and 4th nucleosides, and the bond between the 4th and 5th nucleosides from the 5' side of the 5' flanking region are phosphodiester bonds, and/or the bond between the 1st and 2nd nucleosides, the bond between the 2nd and 3rd nucleosides, and the bond between the 3rd and 4th nucleosides from the 5' side of the 3' flanking region are phosphodiester bonds,

并且其它核苷之间的键全部为硫代磷酸酯键。And the bonds between other nucleosides are all phosphorothioate bonds.

(32)根据(27-1)～(31)中任一项所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其中，侧翼区域包含2’-OMe(2’-O-CH₃)基和/或2’-O-MOE(2’-O-CH₂CH₂OCH₃)基。(32) The antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof according to any one of (27-1) to (31), wherein the flanking region contains a 2'-OMe (2'-O-CH₃ ) group and/or a 2'-O-MOE (2'-O-CH₂ CH₂ OCH₃ ) group.

(33)一种药物组合物，其包含(1)～(32)中任一项所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物。(33) A pharmaceutical composition comprising the antisense oligonucleotide according to any one of (1) to (32) or a pharmaceutically acceptable salt or hydrate thereof.

(34)根据(1)～(32)中任一项所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物、或者(33)所述的药物组合物，其用于治疗和/或预防齿状核红核苍白球路易体萎缩症(DRPLA)。(34) The antisense oligonucleotide according to any one of (1) to (32) or its pharmaceutically acceptable salt or hydrate thereof, or the pharmaceutical composition according to (33), which is used for treating and/or preventing dentatorubral pallidum atrophy with Lewy bodies (DRPLA).

(35)一种治疗和/或预防齿状核红核苍白球路易体萎缩症(DRPLA)的方法，其包括将(1)～(32)中任一项所述的反义寡核苷酸或其药物上可接受的盐或者它们的水合物、或者(33)或(34)所述的药物组合物给药于对象的工序。(35) A method for treating and/or preventing dentatorubral pallidum atrophy with Lewy bodies (DRPLA), comprising the step of administering to a subject the antisense oligonucleotide described in any one of (1) to (32) or its pharmaceutically acceptable salt or hydrate thereof, or the pharmaceutical composition described in (33) or (34).

本发明中，可以提供靶向ATN1 mRNA或pre-mRNA的反义寡核苷酸或其药物上可接受的盐或者它们的水合物、以及包含该反义寡核苷酸或其药物上可接受的盐或者它们的水合物的组合物等。The present invention can provide an antisense oligonucleotide targeting ATN1 mRNA or pre-mRNA, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a composition comprising the antisense oligonucleotide, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

本发明中，可提供由于直接抑制作为DRPLA致病基因的突变ATN1而治疗满意度高的DPLA治疗剂。本发明中，能够以作为DRPLA致病基因的突变ATN1为靶来设计反义寡核苷酸，因此根据本发明的优选方式，可提供副作用少的DRPLA治疗剂。根据本发明的一个方式，还能够基于各患者的基因信息提供个性化治疗。In the present invention, a DPLA therapeutic agent with high treatment satisfaction due to direct inhibition of mutant ATN1, which is a DRPLA pathogenic gene, can be provided. In the present invention, antisense oligonucleotides can be designed with mutant ATN1, which is a DRPLA pathogenic gene, as a target, so according to a preferred embodiment of the present invention, a DRPLA therapeutic agent with few side effects can be provided. According to one embodiment of the present invention, personalized treatment can also be provided based on the genetic information of each patient.

具体实施方式Detailed ways

一个实施方式中，本发明涉及反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1位～第84位、第142位～第168位、第197位～第224位、第286位～第317位、第324位～第370位、第391位～第434位、第519位～第540位、第623位～第643位、第690位～第780位、第824位～第855位、第860位～第897位、第948位～第987位、第1044位～第1072位、第1125位～第1174位、第1181位～第1213位、第1228位～第1255位、第1265位～第1327位、第1334位～第1356位、第1416位～第1440位、第1447位～第1631位、第1638位～第1667位、第1675位～第1705位、第1748位～第1823位、第1838位～第1861位、第1870位～第1913位、第1920位～第1941位、第2000位～第2040位、第2047位～第2075位、第2086位～第2120位、第2129位～第2187位、第2194位～第2415位、第2451位～第2497位、第2592位～第2759位、第2766位～第2870位、第2928位～第2948位、第2955位～第2989位、第3021位～第3086位、第3133位～第3209位、第3217位～第3284位、第3295位～第3350位、第3384位～第3436位、第3562位～第3771位、第3858位～第3905位、第3931位～第4039位、第4067位～第4134位、第4170位～第4232位、第4241位～第4283位和第4286位～第4355位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the present invention relates to an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof, which is composed of 15 to 22 nucleotides and is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 1 to 84, 142 to 168, 197 to 224, 286 to 317, 324 to 370, 391 to 434, 519 to 540, 623 to 643, 690 to 780, 824th to 855th, 860th to 897th, 948th to 987th, 1044th to 1072nd, 1125th to 1174th, 1181st to 1213th, 1228th to 1255th, 1265th to 1327th, 1334th to 1356th, 1416th to 1440th, 1447th to 1631st, 1638th to 1667th, 1675th to 1705th, 1748th to 182 3rd, 1838th to 1861st, 1870th to 1913th, 1920th to 1941st, 2000th to 2040th, 2047th to 2075th, 2086th to 2120th, 2129th to 2187th, 2194th to 2415th, 2451st to 2497th, 2592nd to 2759th, 2766th to 2870th, 2928th to 2948th, 2955th to 2989th, 3rd At least 15 consecutive bases in the target region in the group consisting of positions 021 to 3086, 3133 to 3209, 3217 to 3284, 3295 to 3350, 3384 to 3436, 3562 to 3771, 3858 to 3905, 3931 to 4039, 4067 to 4134, 4170 to 4232, 4241 to 4283 and 4286 to 4355.

序列号471为人atrophin-1(ATN1)的mRNA序列(Gen Bank：NM_001007026)。序列号471的序列为包含4355个碱基的碱基序列，序列号1中，由第1691位～第1747位构成的区域为包含CAG/CAA重复序列的重复区域。一个实施方式中，本发明的反义寡核苷酸的靶序列不包括包含CAG/CAA重复序列的重复区域。Sequence number 471 is the mRNA sequence of human atrophin-1 (ATN1) (Gen Bank: NM_001007026). Sequence number 471 is a base sequence containing 4355 bases, and in sequence number 1, the region consisting of positions 1691 to 1747 is a repeat region containing a CAG/CAA repeat sequence. In one embodiment, the target sequence of the antisense oligonucleotide of the present invention does not include a repeat region containing a CAG/CAA repeat sequence.

一个实施方式中，本发明的反义寡核苷酸与包含靶区域中的至少15个、至少16个、至少17个、至少18个、至少19个、至少20个、例如20个连续的碱基的核酸或由这些碱基构成的核酸互补。In one embodiment, the antisense oligonucleotide of the present invention is complementary to a nucleic acid comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, for example 20 consecutive bases in the target region or a nucleic acid consisting of these bases.

本说明书中，与某核酸“互补”的反义寡核苷酸是指：并不限定于与成为对象的核酸形成沃森-克里克(Watson Crick)型碱基对的反义寡核苷酸，还包括形成摆动碱基对(Wobble base pair)的反义寡核苷酸。此处，沃森-克里克型碱基对是指：在腺嘌呤-胸腺嘧啶、腺嘌呤-尿嘧啶和鸟嘌呤-胞嘧啶之间形成氢键的碱基对，摆动碱基对是指：在鸟嘌呤-尿嘧啶、肌苷-尿嘧啶、肌苷-腺嘌呤和肌苷-胞嘧啶之间形成氢键的碱基对。另外，“互补的碱基序列”可以与成为对象的碱基序列不具有100％的互补性，例如，相对于成为对象的碱基序列，可以包含1个碱基、2个碱基、3个碱基、4个碱基、或5个碱基的非互补的碱基，另外，也可以是与成为对象的碱基序列相比短1个碱基、2个碱基、3个碱基、4个碱基、或5个碱基的碱基序列。一个实施方式中，与某核酸“互补”的反义寡核苷酸相对于该核酸具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、或100％的互补性。本领域技术人员能够容易地确定互补性，例如对2个序列进行比对，对序列之间形成沃森-克里克型碱基对或摆动碱基对的碱基的数量进行计数，用形成了碱基对的碱基的数量除以序列中的碱基的总数，在此基础上乘以100，从而能够算出。In this specification, an antisense oligonucleotide that is "complementary" to a nucleic acid refers to an antisense oligonucleotide that is not limited to an antisense oligonucleotide that forms a Watson-Crick type base pair with the nucleic acid that is the target, and also includes an antisense oligonucleotide that forms a wobble base pair. Here, a Watson-Crick type base pair refers to a base pair that forms a hydrogen bond between adenine-thymine, adenine-uracil, and guanine-cytosine, and a wobble base pair refers to a base pair that forms a hydrogen bond between guanine-uracil, inosine-uracil, inosine-adenine, and inosine-cytosine. In addition, the "complementary base sequence" may not have 100% complementarity with the base sequence to be targeted, for example, it may contain 1 base, 2 bases, 3 bases, 4 bases, or 5 bases of non-complementary bases relative to the base sequence to be targeted, and it may also be a base sequence that is 1 base, 2 bases, 3 bases, 4 bases, or 5 bases shorter than the base sequence to be targeted. In one embodiment, the antisense oligonucleotide that is "complementary" to a nucleic acid has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementarity with the nucleic acid. A person skilled in the art can easily determine complementarity, for example, by aligning two sequences, counting the number of bases that form Watson-Crick base pairs or wobble base pairs between the sequences, dividing the number of bases that form base pairs by the total number of bases in the sequence, and multiplying the result by 100.

作为与某核酸“互补”的反义寡核苷酸的例子，可列举例如在严格的条件下能与该核酸杂交的反义寡核苷酸。本说明书中，“严格的条件”是指：低严格的条件、中严格的条件和高严格的条件中的任意者。“低严格的条件”例如是5×SSC、5×Denhardt溶液、0.5％SDS、50％甲酰胺、32℃的条件。另外，“中严格的条件”例如是5×SSC、5×Denhardt溶液、0.5％SDS、50％甲酰胺、42℃或5×SSC、1％SDS、50mM Tris-HCl(pH7.5)、50％甲酰胺、42℃的条件。“高严格的条件”例如是5×SSC、5×Denhardt溶液、0.5％SDS、50％甲酰胺、50℃或0.2×SSC、0.1％SDS、65℃的条件。在这些条件下，越提高温度，越可以期待有效地得到具有高的序列一致性的碱基序列。然而，作为对杂交的严格性产生影响的要素，考虑到温度、探针浓度、探针的长度、离子强度、时间、盐浓度等多个因素，本领域技术人员通过适宜选择这些要素而能够实现同样的严格性。As an example of an antisense oligonucleotide that is "complementary" to a certain nucleic acid, for example, an antisense oligonucleotide that can hybridize with the nucleic acid under stringent conditions can be cited. In this specification, "stringent conditions" refer to any of low stringency conditions, medium stringency conditions, and high stringency conditions. "Low stringency conditions" are, for example, 5×SSC, 5×Denhardt solution, 0.5% SDS, 50% formamide, 32°C. In addition, "medium stringency conditions" are, for example, 5×SSC, 5×Denhardt solution, 0.5% SDS, 50% formamide, 42°C or 5×SSC, 1% SDS, 50mM Tris-HCl (pH7.5), 50% formamide, 42°C. "High stringency conditions" are, for example, 5×SSC, 5×Denhardt solution, 0.5% SDS, 50% formamide, 50°C or 0.2×SSC, 0.1% SDS, 65°C. Under these conditions, the higher the temperature, the more likely it is that a base sequence with high sequence consistency will be effectively obtained. However, as factors affecting the stringency of hybridization, multiple factors such as temperature, probe concentration, probe length, ionic strength, time, and salt concentration are considered, and those skilled in the art can achieve the same stringency by appropriately selecting these factors.

需要说明的是，杂交中使用市售的试剂盒的情况下，可以使用例如AlkPhosDirectLabelling and Detection System(GE Healthcare公司)。在此情况下，依据试剂盒中随附的方案(protocol)，进行一夜与标记的探针的孵育后，将滤膜在55℃的条件下用包含0.1％(w/v)SDS的1次清洗缓冲液进行清洗后，可以检测杂交。或者，基于靶序列制作探针时，在使用市售的试剂(例如，PCR标记混合物(Roche Diagnostics Co.,Ltd.)等)对该探针进行了地高辛(DIG)标记的情况下，可以使用DIG核酸检测试剂盒(Roche DiagnosticsCo.,Ltd.)等来检测杂交。It should be noted that, when a commercially available kit is used in hybridization, for example, AlkPhos Direct Labelling and Detection System (GE Healthcare) can be used. In this case, after incubation with the labeled probe overnight according to the protocol attached to the kit, the filter membrane is washed with a 1-time washing buffer containing 0.1% (w/v) SDS at 55°C, and hybridization can be detected. Alternatively, when a probe is made based on a target sequence, when the probe is labeled with digoxigenin (DIG) using a commercially available reagent (e.g., PCR labeling mixture (Roche Diagnostics Co., Ltd.), etc., a DIG nucleic acid detection kit (Roche Diagnostics Co., Ltd.) can be used to detect hybridization.

需要说明的是，碱基序列的一致性可以使用基于Carlin和Arthur的算法BLAST(Basic Local Alignment Search Tool)(Proc.Natl.Acad.Sci.USA 872264-2268,1990；Proc Natl Acad Sci USA90：5873,1993)来确定。开发出了基于BLAST的算法的被称为BLASTN、BLASTX的程序(Altschul SF,et al：J Mol Biol 215：403,1990)。使用BLASTN对碱基序列进行解析的情况下，参数设为例如评分＝100、字长＝12。使用BLAST和Gapped BLAST程序的情况下，使用各程序的缺省参数。It should be noted that the identity of the base sequence can be determined using the BLAST (Basic Local Alignment Search Tool) algorithm based on Carlin and Arthur (Proc. Natl. Acad. Sci. USA 872264-2268, 1990; Proc Natl Acad Sci USA90: 5873, 1993). Programs called BLASTN and BLASTX based on the BLAST algorithm have been developed (Altschul SF, et al: J Mol Biol 215: 403, 1990). When using BLASTN to analyze the base sequence, the parameters are set to, for example, score = 100 and word length = 12. When using BLAST and Gapped BLAST programs, the default parameters of each program are used.

一个实施方式中，本发明的反义寡核苷酸可以为例如15个核苷酸长度以上、16个核苷酸长度以上、17个核苷酸长度以上、18个核苷酸长度以上、19个核苷酸长度以上、20个核苷酸长度以上、21个核苷酸长度以上、22个核苷酸长度以上、23个核苷酸长度以上、24个核苷酸长度以上、25个核苷酸长度以上、26个核苷酸长度以上、27个核苷酸长度以上、28个核苷酸长度以上、29个核苷酸长度以上或30个核苷酸长度，可以为30个核苷酸长度以下、29个核苷酸长度以下、28个核苷酸长度以下、27个核苷酸长度以下、26个核苷酸长度以下、25个核苷酸长度以下、24个核苷酸长度以下、23个核苷酸长度以下、22个核苷酸长度以下、21个核苷酸长度以下、20个核苷酸长度以下、19个核苷酸长度以下、18个核苷酸长度以下、17个核苷酸长度以下、16个核苷酸长度以下或15个核苷酸长度。本发明的反义寡核苷酸例如可以由15～30个核苷酸、15～25个核苷酸、15～24个核苷酸、15～23个核苷酸、15～22个核苷酸、15～21个核苷酸、15～20个核苷酸、16～25个核苷酸、17～25个核苷酸、18～25个核苷酸、19～25个核苷酸、20～25个核苷酸、16～24个核苷酸、17～23个核苷酸、18～22个核苷酸、19～21个核苷酸、例如20个核苷酸构成。In one embodiment, the antisense oligonucleotide of the present invention can be, for example, 15 nucleotides in length or more, 16 nucleotides in length or more, 17 nucleotides in length or more, 18 nucleotides in length or more, 19 nucleotides in length or more, 20 nucleotides in length or more, 21 nucleotides in length or more, 22 nucleotides in length or more, 23 nucleotides in length or more, 24 nucleotides in length or more, 25 nucleotides in length or more, 26 nucleotides in length or more, 27 nucleotides in length or more, 28 nucleotides in length or more, 29 nucleotides in length or more, or 30 nucleotides in length, or less than 30 nucleotides in length, or less than 29 nucleotides in length, or less than 28 nucleotides in length, or less than 27 nucleotides in length, or less than 26 nucleotides in length, or less than 25 nucleotides in length, or less than 24 nucleotides in length, or less than 23 nucleotides in length, or less than 22 nucleotides in length, or less than 21 nucleotides in length, or less than 20 nucleotides in length, or less than 19 nucleotides in length, or less than 18 nucleotides in length, or less than 17 nucleotides in length, or less than 16 nucleotides in length, or less than 15 nucleotides in length. The antisense oligonucleotide of the present invention can be composed of, for example, 15 to 30 nucleotides, 15 to 25 nucleotides, 15 to 24 nucleotides, 15 to 23 nucleotides, 15 to 22 nucleotides, 15 to 21 nucleotides, 15 to 20 nucleotides, 16 to 25 nucleotides, 17 to 25 nucleotides, 18 to 25 nucleotides, 19 to 25 nucleotides, 20 to 25 nucleotides, 16 to 24 nucleotides, 17 to 23 nucleotides, 18 to 22 nucleotides, 19 to 21 nucleotides, for example, 20 nucleotides.

作为本发明的反义寡核苷酸的药学上可接受的盐的例子，可列举钠盐、钾盐、锂盐之类的碱金属盐、钙盐、镁盐之类的碱土金属盐；铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等金属盐；铵盐；叔辛胺盐、二苄胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己胺盐、N,N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基铵盐、三(羟基甲基)氨基甲烷盐之类的有机胺盐；氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐之类的氢卤酸盐；硝酸盐、高氯酸盐、硫酸盐、磷酸盐等无机酸盐；甲磺酸盐、三氟甲磺酸盐、乙磺酸盐之类的低级烷烃磺酸盐；苯磺酸盐、对甲苯磺酸盐之类的芳基磺酸盐；乙酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等有机酸盐；甘氨酸盐、赖氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐之类的氨基酸盐等。这些盐可以利用公知的方法来制造。或者，本发明的反义寡核苷酸也可以是其水合物的形态。Examples of pharmaceutically acceptable salts of the antisense oligonucleotides of the present invention include alkali metal salts such as sodium salts, potassium salts, and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; ammonium salts; tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, and tetramethylammonium salts. , organic amine salts such as tris(hydroxymethyl)aminomethane salt; hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; aryl sulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate. These salts can be made using known methods. Alternatively, the antisense oligonucleotide of the present invention can also be in the form of its hydrate.

本发明的反义寡核苷酸以核苷酸作为结构单元，上述核苷酸可以是核糖核苷酸、脱氧核糖核苷酸、或修饰核苷酸中的任意者。The antisense oligonucleotide of the present invention uses nucleotides as structural units, and the nucleotides may be ribonucleotides, deoxyribonucleotides, or modified nucleotides.

修饰核苷酸是指：构成核糖核苷酸或脱氧核糖核苷酸的核酸碱基、糖部分及磷酸键部分中的全部或一部分进行了修饰的核苷酸。A modified nucleotide refers to a nucleotide in which all or part of the nucleic acid base, sugar moiety, and phosphate bond moiety constituting a ribonucleotide or a deoxyribonucleotide are modified.

作为核酸碱基，例如可以列举出腺嘌呤、鸟嘌呤、次黄嘌呤、胞嘧啶、胸腺嘧啶、尿嘧啶、或它们的修饰碱基。作为上述修饰碱基，例如可列举假尿嘧啶、3-甲基尿嘧啶、二氢尿嘧啶、5-烷基胞嘧啶(例如，5-甲基胞嘧啶)、5-烷基尿嘧啶(例如，5-乙基尿嘧啶)、5-卤代尿嘧啶(例如，5-溴代尿嘧啶)、6-氮杂嘧啶、6-烷基嘧啶(例如，6-甲基尿嘧啶)、2-硫代尿嘧啶、4-硫代尿嘧啶、4-乙酰基胞嘧啶、5-(羧基羟基甲基)尿嘧啶、5-羧基甲基氨基甲基-2-硫代尿嘧啶、5-羧基甲基氨基甲基尿嘧啶、1-甲基腺嘌呤、1-甲基次黄嘌呤、2,2-二甲基鸟嘌呤、3-甲基胞嘧啶、2-甲基腺嘌呤、2-甲基鸟嘌呤、N6-甲基腺嘌呤、7-甲基鸟嘌呤、5-甲氧基氨基甲基-2-硫代尿嘧啶、5-甲基氨基甲基尿嘧啶、5-甲基羰基甲基尿嘧啶、5-甲基氧基尿嘧啶、5-甲基-2-硫代尿嘧啶、2-甲基硫基-N6-异戊烯基腺嘌呤、尿嘧啶-5-氧基乙酸、2-硫代胞嘧啶、嘌呤、2,6-二氨基嘌呤、2-氨基嘌呤、异鸟嘌呤、吲哚、咪唑、黄嘌呤等，但不限于这些。As nucleic acid bases, for example, adenine, guanine, hypoxanthine, cytosine, thymine, uracil, or modified bases thereof can be listed. As the above-mentioned modified bases, for example, pseudouracil, 3-methyluracil, dihydrouracil, 5-alkylcytosine (e.g., 5-methylcytosine), 5-alkyluracil (e.g., 5-ethyluracil), 5-halouracil (e.g., 5-bromouracil), 6-azapyrimidine, 6-alkylpyrimidine (e.g., 6-methyluracil), 2-thiouracil, 4-thiouracil, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyluracil, 1-methyladenine, 1-methyl The invention also includes, but is not limited to, 2,6-diaminopurine, 2-aminopurine, 3-methylcytosine, 2-methyladenine, 2-methylguanine, N6-methyladenine, 7-methylguanine, 5-methoxyaminomethyl-2-thiouracil, 5-methylaminomethyluracil, 5-methylcarbonylmethyluracil, 5-methyloxyuracil, 5-methyl-2-thiouracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid, 2-thiocytosine, purine, 2,6-diaminopurine, 2-aminopurine, isoguanine, indole, imidazole, xanthine, etc.

本说明书中，胸腺嘧啶“T”与尿嘧啶“U”可以互换，是“T”还是“U”并不会对本发明的反义寡核苷酸的活性产生本质性影响，因此也包括本说明书中所示的碱基序列中“T”为“U”的情况在内，用相同的序列号表示。另外，本说明书中，包含修饰碱基的序列与不包含修饰碱基的序列用相同的序列号表示，例如“胞嘧啶”与“甲基胞嘧啶”可以互换，“胞嘧啶”为“甲基胞嘧啶”的情况下，也用相同的序列号表示。In this specification, thymine "T" and uracil "U" are interchangeable, and whether it is "T" or "U" does not have an essential effect on the activity of the antisense oligonucleotide of the present invention, so the same sequence number is used to represent the base sequence shown in this specification, including the case where "T" is "U". In addition, in this specification, a sequence containing a modified base and a sequence not containing a modified base are represented by the same sequence number, for example, "cytosine" and "methylcytosine" are interchangeable, and when "cytosine" is "methylcytosine", it is also represented by the same sequence number.

作为糖部分的修饰，例如可以列举出核糖的2’位的修饰和糖的其它部分的修饰。作为核糖的2’位的修饰，例如可以列举出将核糖的2’位的-OH基置换为-OR、-OROR、-R、-R’OR、-SH、-SR、-NH₂、-NHR、-NR₂、-N₃、-CN、-F、-Cl、-Br、-I、例如-OMe(-O-CH₃)或-O甲氧基乙基(-O-MOE：-O-CH₂CH₂OCH₃)的修饰。此处，R表示烷基、环烷基、酰基或芳基。R’表示亚烷基。Examples of modifications of the sugar moiety include modifications of the 2'-position of ribose and modifications of other sugar moieties. Examples of modifications of the 2'-position of ribose include substitution of the -OH group at the 2'-position of ribose with -OR, -OROR, -R, -R'OR, -SH, -SR, -NH₂ , -NHR, -NR₂ , -N₃ , -CN, -F, -Cl, -Br, -I, for example, -OMe (-O-CH₃ ) or -O-methoxyethyl (-O-MOE: -O-CH₂ CH₂ OCH₃ ). Here, R represents an alkyl group, a cycloalkyl group, an acyl group or an aryl group. R' represents an alkylene group.

作为糖的其它部分的修饰，例如可列举将核糖或脱氧核糖的4’位的O置换为S的修饰、使糖的2’位和4’位交联的修饰、例如LNA(锁核酸，Locked Nucleic Acid)或ENA(2’-O,4’-C-Ethylene-bridged Nucleic Acids)等，但不限定于这些。Examples of modifications of other parts of the sugar include, but are not limited to, substitution of O at the 4'-position of ribose or deoxyribose with S, and cross-linking of the 2'-position and 4'-position of the sugar, such as LNA (locked nucleic acid) or ENA (2'-O, 4'-C-Ethylene-bridged Nucleic Acids).

作为磷酸键部分的修饰，例如可以列举出将磷酸二酯键置换为硫代磷酸酯键、二硫代磷酸酯键、烷基膦酸酯键、亚磷酰胺键、硼代磷酸酯键(例如参照Enya et al：Bioorganic&Medicinal Chemistry,2008,18,9154-9160)的修饰(例如参照日本再公表专利公报第2006/129594号和日本再公表专利公报第2006/038608号)。Examples of modifications of the phosphate bond portion include replacement of the phosphodiester bond with a phosphorothioate bond, a phosphorodithioate bond, an alkylphosphonate bond, a phosphoramidite bond, or a boranophosphate bond (see, for example, Enya et al: Bioorganic & Medicinal Chemistry, 2008, 18, 9154-9160) (see, for example, Japanese Re-Publication Patent Gazette No. 2006/129594 and Japanese Re-Publication Patent Gazette No. 2006/038608).

本说明书中，作为烷基，优选直链状或支链状的碳数1～6的烷基。具体而言，例如可列举甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、正己基、异己基。该烷基可以被取代，作为上述取代基，例如可以列举出卤素、烷氧基、氰基、硝基，可以被1～3个这些基团取代。In the present specification, the alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, and isohexyl. The alkyl group may be substituted, and examples of the substituent include halogen, alkoxy, cyano, and nitro, and may be substituted by 1 to 3 of these groups.

本说明书中，作为环烷基，优选碳数3～12的环烷基。具体而言，例如可列举环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基。In the present specification, the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and a cyclododecyl group.

本说明书中，作为卤素，可以列举出氟、氯、溴、碘。In the present specification, examples of the halogen include fluorine, chlorine, bromine and iodine.

本说明书中，作为烷氧基，可以列举出直链状或支链状的碳数1～6的烷氧基、例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊基氧基、异戊基氧基、正己基氧基、异己基氧基等。尤其优选碳数1～3的烷氧基。In the present specification, examples of the alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, etc. Alkoxy groups having 1 to 3 carbon atoms are particularly preferred.

本说明书中，作为芳基，优选碳数6～10的芳基。具体而言，例如可以列举出苯基、α-萘基、β-萘基。尤其优选苯基。该芳基可以被取代，作为上述取代基，例如可以列举出烷基、卤素、烷氧基、氰基、硝基，可以被1～3个这些基团取代。In the present specification, the aryl group is preferably an aryl group having 6 to 10 carbon atoms. Specifically, for example, phenyl, α-naphthyl, and β-naphthyl can be listed. Phenyl is particularly preferred. The aryl group may be substituted, and as the substituent, for example, alkyl, halogen, alkoxy, cyano, and nitro can be listed, and 1 to 3 of these groups can be substituted.

本说明书中，作为亚烷基，优选直链状或支链状的碳数1～6的亚烷基。具体而言，例如可以列举出亚甲基、亚乙基、三亚甲基、四亚甲基、五亚甲基、六亚甲基、2-(乙基)三亚甲基、1-(甲基)四亚甲基。In the present specification, the alkylene group is preferably a linear or branched alkylene group having 1 to 6 carbon atoms, and specific examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 2-(ethyl)trimethylene, and 1-(methyl)tetramethylene.

本说明书中，作为酰基，可以列举出直链状或支链状的烷酰基或芳酰基。作为烷酰基，例如可列举甲酰基、乙酰基、2-甲基乙酰基、2,2-二甲基乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、2,2-二甲基丙酰基、己酰基等。作为芳酰基，例如可以列举出苯甲酰基、甲苯甲酰基、萘甲酰基。上述芳酰基可以在可取代的位置处被取代，可以被烷基取代。In this specification, as the acyl group, a linear or branched alkanoyl group or an aroyl group can be cited. As the alkanoyl group, for example, a formyl group, an acetyl group, a 2-methylacetyl group, a 2,2-dimethylacetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, a 2,2-dimethylpropionyl group, a hexanoyl group, etc. can be cited. As the aroyl group, for example, a benzoyl group, a toluoyl group, and a naphthoyl group can be cited. The above aroyl group can be substituted at a substitutable position and can be substituted by an alkyl group.

一个实施方式中，本发明的反义寡核苷酸是包含中间的间隔区域和与间隔区域的5’末端侧和3’末端侧相邻的2个侧翼区域(也分别记为5’侧翼区域和3’侧翼区域)的间隔寡核苷酸。间隔区域是被RNase H识别的区域，由糖部未被修饰的脱氧核糖核苷酸构成。侧翼区域包含至少一个修饰核苷酸，例如其全部由修饰核苷酸(例如修饰了核糖的2’位的核糖核苷酸)构成。一个实施方式中，5’侧翼区域和3’侧翼区域的核苷分别包含至少一个、例如二个以上、三个以上、四个以上、五个以上的糖部分的修饰、例如2’-OMe基和/或2’-O-MOE基，例如5’侧翼区域和3’侧翼区域的核苷也可以全部包含2’-OMe基和/或2’-O-MOE基。另外，5’侧翼区域和3’侧翼区域的核苷可以在碱基部分包含修饰，例如可以包含至少一个甲基胞嘧啶。In one embodiment, the antisense oligonucleotide of the present invention is a spacer oligonucleotide comprising a middle spacer region and two flanking regions adjacent to the 5' terminal side and the 3' terminal side of the spacer region (also respectively recorded as 5' flanking region and 3' flanking region). The spacer region is a region recognized by RNase H and is composed of deoxyribonucleotides whose sugar part is not modified. The flanking region contains at least one modified nucleotide, for example, all of which are composed of modified nucleotides (for example, ribonucleotides at the 2' position of the ribose modified). In one embodiment, the nucleosides in the 5' flanking region and the 3' flanking region respectively contain at least one, for example, two or more, three or more, four or more, or five or more modifications of the sugar part, for example, 2'-OMe base and/or 2'-O-MOE base, for example, the nucleosides in the 5' flanking region and the 3' flanking region can also all contain 2'-OMe base and/or 2'-O-MOE base. In addition, the nucleosides in the 5' flanking region and the 3' flanking region can contain modifications in the base part, for example, at least one methylcytosine can be contained.

间隔区域的长度没有限定，例如可以为5～15个、8～12个、9～11个或10个碱基长度。5’侧翼区域和3’侧翼区域的长度没有限定，例如可以分别独立地为2～10个、3～8个、4～6个或5个碱基长度。一个实施方式中，间隔区域的长度为10个碱基长度，5’侧翼区域和3’侧翼区域的长度分别为5个碱基长度。The length of the spacer region is not limited, and can be, for example, 5 to 15, 8 to 12, 9 to 11 or 10 bases in length. The length of the 5' flanking region and the 3' flanking region is not limited, and can be, for example, 2 to 10, 3 to 8, 4 to 6 or 5 bases in length, respectively. In one embodiment, the length of the spacer region is 10 bases in length, and the length of the 5' flanking region and the 3' flanking region are 5 bases in length, respectively.

一个实施方式中，本发明的间隔寡核苷酸包含一个以上的磷酸键部分的修饰、例如硫代磷酸酯键，例如可以是核苷酸之间的键中的一个以上、二个以上、三个以上、四个以上、五个以上、十个以上、十五个以上、例如全部为硫代磷酸酯键。一个实施方式中，本发明的间隔寡核苷酸中，核苷之间的键全部为硫代磷酸酯键。一个实施方式中，本发明的间隔寡核苷酸在一个以上、二个以上、三个以上、四个以上、五个以上、六个以上、七个以上、八个以上、九个以上、或十个以上(例如两个～六个)、例如5’侧翼区域和/或3’侧翼区域包含磷酸二酯键，并且其它核苷之间的键全部为硫代磷酸酯键。一个实施方式中，从5’侧翼区域的5’侧起的第2位与第3位的核苷之间的键、第3位与第4位的核苷之间的键和第4位与第5位的核苷之间的键中的一个以上为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第1位与第2位的核苷之间的键、第2位与第3位的核苷之间的键和第3位与第4位的核苷之间的键中的一个以上为磷酸二酯键，并且其它核苷之间的键全部为硫代磷酸酯键。一个实施方式中，从5’侧翼区域的5’侧起的第2位与第3位的核苷之间的键和第4位与第5位的核苷之间的键为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第1位与第2位的核苷之间的键和第3位与第4位的核苷之间的键为磷酸二酯键，并且其它核苷之间的键全部为硫代磷酸酯键。一个实施方式中，从5’侧翼区域的5’侧起的第2位与第3位的核苷之间的键、第3位与第4位的核苷之间的键和第4位与第5位的核苷之间的键为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第1位与第2位的核苷之间的键、第2位与第3位的核苷之间的键和第3位与第4位的核苷之间的键为磷酸二酯键，并且其它核苷之间的键全部为硫代磷酸酯键。一个实施方式中，从5’侧翼区域的5’侧起的第2位与第3位的核苷之间的键和第3位与第4位的核苷之间的键为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第2位与第3位的核苷之间的键和第3位与第4位的核苷之间的键为磷酸二酯键，并且其它核苷之间的键全部为硫代磷酸酯键。一个实施方式中，从5’侧翼区域的5’侧向第3位与第4位的核苷之间的键和第4位与第5位的核苷之间的键为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第1位与第2位的核苷之间的键和第2位与第3位的核苷之间的键为磷酸二酯键，并且其它核苷之间的键全部为硫代磷酸酯键。一个实施方式中，从5’侧翼区域的5’侧起的第2位与第3位的核苷之间的键为磷酸二酯键，以及/或者从3’侧翼区域的5’侧向第3位与第4位的核苷之间的键为磷酸二酯键，并且其它核苷之间的键全部为硫代磷酸酯键。一个实施方式中，从5’侧翼区域的5’侧向第3位与第4位的核苷之间的键为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第2位与第3位的核苷之间的键为磷酸二酯键，并且其它核苷之间的键全部为硫代磷酸酯键。一个实施方式中，从5’侧翼区域的5’侧向第4位与第5位的核苷之间的键为磷酸二酯键，以及/或者从3’侧翼区域的5’侧起的第1位与第2位的核苷之间的键为磷酸二酯键，并且其它核苷之间的键全部为硫代磷酸酯键。一个实施方式中，本发明的间隔寡核苷酸可以不含磷酸键部分的修饰且核苷酸之间的键全部为磷酸二酯键。In one embodiment, the spacer oligonucleotide of the present invention comprises a modification of one or more phosphate bond portions, such as a phosphorothioate bond, for example, one or more, two or more, three or more, four or more, five or more, ten or more, fifteen or more, for example, all of the bonds between nucleotides are phosphorothioate bonds. In one embodiment, in the spacer oligonucleotide of the present invention, all of the bonds between nucleosides are phosphorothioate bonds. In one embodiment, the spacer oligonucleotide of the present invention comprises a phosphodiester bond in one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more (e.g., two to six), such as the 5' flanking region and/or the 3' flanking region, and all of the bonds between other nucleosides are phosphorothioate bonds. In one embodiment, one or more of the bond between the 2nd and 3rd nucleosides from the 5' side of the 5' flanking region, the bond between the 3rd and 4th nucleosides, and the bond between the 4th and 5th nucleosides is a phosphodiester bond, and/or one or more of the bond between the 1st and 2nd nucleosides from the 5' side of the 3' flanking region, the bond between the 2nd and 3rd nucleosides, and the bond between the 3rd and 4th nucleosides is a phosphodiester bond, and all the bonds between the other nucleosides are phosphorothioate bonds. In one embodiment, the bond between the 2nd and 3rd nucleosides from the 5' side of the 5' flanking region and the bond between the 4th and 5th nucleosides are phosphodiester bonds, and/or the bond between the 1st and 2nd nucleosides from the 5' side of the 3' flanking region and the bond between the 3rd and 4th nucleosides are phosphodiester bonds, and all the bonds between the other nucleosides are phosphorothioate bonds. In one embodiment, the bond between the 2nd and 3rd nucleosides from the 5' side of the 5' flanking region, the bond between the 3rd and 4th nucleosides, and the bond between the 4th and 5th nucleosides are phosphodiester bonds, and/or the bond between the 1st and 2nd nucleosides from the 5' side of the 3' flanking region, the bond between the 2nd and 3rd nucleosides, and the bond between the 3rd and 4th nucleosides are phosphodiester bonds, and all the bonds between the other nucleosides are phosphorothioate bonds. In one embodiment, the bond between the 2nd and 3rd nucleosides from the 5' side of the 5' flanking region and the bond between the 3rd and 4th nucleosides are phosphodiester bonds, and/or the bond between the 2nd and 3rd nucleosides from the 5' side of the 3' flanking region and the bond between the 3rd and 4th nucleosides are phosphodiester bonds, and all the bonds between the other nucleosides are phosphorothioate bonds. In one embodiment, the bond between the nucleoside at the 3rd and 4th positions from the 5' side of the 5' flanking region and the bond between the nucleoside at the 4th and 5th positions are phosphodiester bonds, and/or the bond between the nucleoside at the 1st and 2nd positions from the 5' side of the 3' flanking region and the bond between the nucleoside at the 2nd and 3rd positions are phosphodiester bonds, and all the bonds between the other nucleosides are phosphorothioate bonds. In one embodiment, the bond between the nucleoside at the 2nd and 3rd positions from the 5' side of the 5' flanking region is a phosphodiester bond, and/or the bond between the nucleoside at the 3rd and 4th positions from the 5' side of the 3' flanking region is a phosphodiester bond, and all the bonds between the other nucleosides are phosphorothioate bonds. In one embodiment, the bond between the nucleosides at the 3rd and 4th positions from the 5' side of the 5' flanking region is a phosphodiester bond, and/or the bond between the nucleosides at the 2nd and 3rd positions from the 5' side of the 3' flanking region is a phosphodiester bond, and all the bonds between the other nucleosides are phosphorothioate bonds. In one embodiment, the bond between the nucleosides at the 4th and 5th positions from the 5' side of the 5' flanking region is a phosphodiester bond, and/or the bond between the nucleosides at the 1st and 2nd positions from the 5' side of the 3' flanking region is a phosphodiester bond, and all the bonds between the other nucleosides are phosphorothioate bonds. In one embodiment, the spacer oligonucleotide of the present invention may not contain modification of the phosphate bond portion and all the bonds between the nucleotides are phosphodiester bonds.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1位～第84位、第142位～第168位、第197位～第224位、第286位～第317位、第324位～第370位、第391位～第434位、第519位～第540位、第623位～第643位、第690位～第780位、第824位～第855位、第860位～第897位、第948位～第987位、第1044位～第1072位、第1125位～第1174位、第1181位～第1213位、第1228位～第1255位、第1265位～第1327位、第1334位～第1356位、第1416位～第1440位、第1447位～第1631位、第1638位～第1667位、第1675位～第1705位、第1748位～第1823位、第1838位～第1861位、第1870位～第1913位、第1920位～第1941位、第2000位～第2040位、第2047位～第2075位、第2086位～第2120位、第2129位～第2187位、第2194位～第2415位、第2451位～第2497位、第2592位～第2759位、第2766位～第2870位、第2928位～第2948位、第2955位～第2989位、第3021位～第3086位、第3133位～第3209位、第3217位～第3284位、第3295位～第3350位、第3384位～第3436位、第3562位～第3771位、第3858位～第3905位、第3931位～第4039位、第4067位～第4134位、第4170位～第4232位、第4241位～第4283位和第4286位～第4355位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 1 to 84, 142 to 168, 197 to 224, 286 to 317, 324 to 370, 391 to 434, 519 to 540, 623 to 643, 690 to 780, 824 to 855, 860 to 897, and 1030 selected from the base sequence of SEQ ID NO: 471. 948th to 987th, 1044th to 1072nd, 1125th to 1174th, 1181st to 1213th, 1228th to 1255th, 1265th to 1327th, 1334th to 1356th, 1416th to 1440th, 1447th to 1631st, 1638th to 1667th, 1675th to 1705th, 1748th to 1823rd, 1838th to 1861st, 1870th to 1913th, 1920th to 1941st, 2000th to 2040th, 2047th to 2075th, 2086th to 2120th, 2129th to 2187th, 2194th to 2415th, 2451st to 2497th, 2592nd to 2759th, 2766th to 2870th, 2928th to 2948th, 2955th to 2989th, 3021st to 30 86, 3133-3209, 3217-3284, 3295-3350, 3384-3436, 3562-3771, 3858-3905, 3931-4039, 4067-4134, 4170-4232, 4241-4283 and 4286-4355.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1位～第84位、第142位～第168位、第391位～第434位、第697位～第780位、第962位～第980位、第1125位～第1174位、第1181位～第1213位、第1228位～第1255位、第1265位～第1320位、第1454位～第1631位、第1682位～第1705位、第1748位～第1816位、第1870位～第1913位、第2015位～第2040位、第2086位～第2120位、第2129位～第2187位、第2201位～第2408位、第2592位～第2759位、第2773位～第2870位、第2955位～第2982位、第3028位～第3079位、第3133位～第3209位、第3224位～第3277位、第3295位～第3350位、第3391位～第3429位、第3562位～第3771位、第3865位～第3898位、第3938位～第4032位、第4074位～第4127位和第4170位～第4225位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 1 to 84, 142 to 168, 391 to 434, 697 to 780, 962 to 980, 1125 to 1174, 1181 to 1213, 1228 to 1255, 1265 to 1320, 1454 to 1631, 1682 to 1705, 1748 to 1816, 1870 to 1913, 2015 to 2040, 2086 to 2091, At least 15 consecutive bases in the target region in the group consisting of positions 2120, 2129 to 2187, 2201 to 2408, 2592 to 2759, 2773 to 2870, 2955 to 2982, 3028 to 3079, 3133 to 3209, 3224 to 3277, 3295 to 3350, 3391 to 3429, 3562 to 3771, 3865 to 3898, 3938 to 4032, 4074 to 4127 and 4170 to 4225.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1位～第69位、第331位～第363位、第398位～第427位、第697位～第773位、第867位～第890位、第955位～第980位、第1132位～第1167位、第1272位～第1320位、第1454位～第1624位、第1682位～第1705位、第1748位～第1816位、第1877位～第1906位、第2007位～第2033位、第2093位～第2113位、第2136位～第2180位、第2201位～第2408位、第2458位～第2490位、第2599位～第2752位、第2773位～第2863位、第2962位～第2982位、第3028位～第3079位、第3140位～第3202位、第3224位～第3277位、第3302位～第3343位、第3391位～第3429位、第3569位～第3764位、第3865位～第3898位、第3938位～第4032位、第4074位～第4127位、第4177位～第4225位、第4248位～第4276位和第4293位～第4355位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 1 to 69, 331 to 363, 398 to 427, 697 to 773, 867 to 890, 955 to 980, 1132 to 1167, 1272 to 1320, 1454 to 1624, 1682 to 1705, 1748 to 1816, 1877 to 1906, 2007 to 2033, 2093 to 2113, 2136 to 2180, 2201 to 2267, 2277 to 2281, 2291 to 2303, 2317 to 2324, 2330 to 2341, 2361 to 2370, 2381 to 2391, 2413 to 2433, 2447 to 2450, 2471 to 2481, 2490 to 2500, 2511 to 2521, 2532 to 2541, 2554 to 2561, 2571 to 2581 2408, 2458-2490, 2599-2752, 2773-2863, 2962-2982, 3028-3079, 3140-3202, 3224-3277, 3302-3343, 3391-3429, 3569-3764, 3865-3898, 3938-4032, 4074-4127, 4177-4225, 4248-4276, and 4293-4355. At least 15 consecutive bases in the target region.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1位～第69位、第398位～第427位、第697位～第773位、第1132位～第1167位、第1272位～第1320位、第1454位～第1624位、第1682位～第1705位、第1748位～第1816位、第1877位～第1906位、第2093位～第2113位、第2136位～第2180位、第2201位～第2408位、第2599位～第2752位、第2773位～第2863位、第2962位～第2982位、第3028位～第3079位、第3140位～第3202位、第3224位～第3277位、第3302位～第3343位、第3391位～第3429位、第3569位～第3764位、第3865位～第3898位、第3938位～第4032位和第4177位～第4225位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 1 to 69, 398 to 427, 697 to 773, 1132 to 1167, 1272 to 1320, 1454 to 1624, 1682 to 1705, 1748 to 1816, 1877 to 1906, 2093 to 2113, 2136 to 2180, 2201 to 2317, 2327 to 2331, 2340 to 2361, 2371 to 2380, 2391 to 2413, 2437 to 2443, 2450 to 2461, 2471 to 2480, 2491 to 2501, 2513 to 2521, 2532 to 2533, 2544 to 2561, 2571 to 2581, 2591 to 2613, 2636 to 2643, 2650 to 2664, 2671 to 2675 At least 15 consecutive bases in the target region of the group consisting of positions 1 to 2408, 2599 to 2752, 2773 to 2863, 2962 to 2982, 3028 to 3079, 3140 to 3202, 3224 to 3277, 3302 to 3343, 3391 to 3429, 3569 to 3764, 3865 to 3898, 3938 to 4032, and 4177 to 4225.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第54位～第73位、第148位～第167位、第397位～第432位、第723位～第742位、第747位～第778位、第965位～第984位、第1127位～第1146位、第1148位～第1173位、第1182位～第1213位、第1228位～第1254位、第1270位～第1308位、第1484位～第1564位、第1578位～第1629位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1870位～第1913位、第2015位～第2034位、第2086位～第2118位、第2129位～第2148位、第2151位～第2184位、第2206位～第2225位、第2239位～第2272位、第2287位～第2336位、第2337位～第2373位、第2387位～第2406位、第2598位～第2757位、第2775位～第2809位、第2826位～第2866位、第2959位～第2982位、第3032位～第3051位、第3052位～第3071位、第3136位～第3155位、第3168位～第3187位、第3188位～第3207位、第3232位～第3270位、第3298位～第3344位、第3408位～第3427位、第3563位～第3582位、第3590位～第3728位、第3739位～第3769位、第3877位～第3896位、第3949位～第4030位和第4170位～第4225位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 432, 723 to 742, 747 to 778, 965 to 984, 1127 to 1146, 1148 to 1173, 1182 to 12 13th, 1228th to 1254th, 1270th to 1308th, 1484th to 1564th, 1578th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1913th, 2015th to 2034th, 2086th to 2118th, 2129th to 2148th, 215 1st to 2184th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2598th to 2757th, 2775th to 2809th, 2826th to 2866th, 2959th to 2982nd, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3155th , 3168th to 3187th, 3188th to 3207th, 3232nd to 3270th, 3298th to 3344th, 3408th to 3427th, 3563rd to 3582nd, 3590th to 3728th, 3739th to 3769th, 3877th to 3896th, 3949th to 4030th and 4170th to 4225th.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第54位～第73位、第148位～第167位、第397位～第416位、第398位～第417位、第399位～第418位、第400位～第419位、第401位～第420位、第402位～第421位、第403位～第422位、第404位～第423位、第405位～第424位、第406位～第425位、第407位～第426位、第408位～第427位、第413位～第432位、第723位～第742位、第747位～第766位、第756位～第775位、第759位～第778位、第965位～第984位、第1127位～第1146位、第1148位～第1167位、第1151位～第1170位、第1154位～第1173位、第1182位～第1201位、第1185位～第1204位、第1188位～第1207位、第1191位～第1210位、第1194位～第1213位、第1228位～第1247位、第1231位～第1250位、第1235位～第1254位、第1270位～第1289位、第1289位～第1308位、第1484位～第1503位、第1488位～第1507位、第1491位～第1510位、第1493位～第1512位、第1506位～第1525位、第1517位～第1536位、第1531位～第1550位、第1545位～第1564位、第1578位～第1597位、第1579位～第1598位、第1580位～第1599位、第1581位～第1600位、第1582位～第1601位、第1583位～第1602位、第1584位～第1603位、第1585位～第1604位、第1586位～第1605位、第1587位～第1606位、第1588位～第1607位、第1589位～第1608位、第1590位～第1609位、第1591位～第1610位、第1592位～第1611位、第1593位～第1612位、第1594位～第1613位、第1595位～第1614位、第1596位～第1615位、第1597位～第1616位、第1598位～第1617位、第1599位～第1618位、第1600位～第1619位、第1601位～第1620位、第1602位～第1621位、第1603位～第1622位、第1604位～第1623位、第1605位～第1624位、第1607位～第1626位、第1610位～第1629位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1870位～第1889位、第1871位～第1890位、第1874位～第1893位、第1877位～第1896位、第1878位～第1897位、第1879位～第1898位、第1880位～第1899位、第1881位～第1900位、第1882位～第1901位、第1883位～第1902位、第1884位～第1903位、第1885位～第1904位、第1886位～第1905位、第1887位～第1906位、第1889位～第1908位、第1894位～第1913位、第2015位～第2034位、第2086位～第2105位、第2093位～第2112位、第2094位～第2113位、第2097位～第2116位、第2099位～第2118位、第2129位～第2148位、第2151位～第2170位、第2165位～第2184位、第2206位～第2225位、第2239位～第2258位、第2253位～第2272位、第2287位～第2306位、第2301位～第2320位、第2317位～第2336位、第2337位～第2356位、第2354位～第2373位、第2387位～第2406位、第2598位～第2617位、第2613位～第2632位、第2614位～第2633位、第2615位～第2634位、第2616位～第2635位、第2617位～第2636位、第2618位～第2637位、第2619位～第2638位、第2620位～第2639位、第2621位～第2640位、第2622位～第2641位、第2623位～第2642位、第2624位～第2643位、第2625位～第2644位、第2626位～第2645位、第2627位～第2646位、第2628位～第2647位、第2629位～第2648位、第2630位～第2649位、第2631位～第2650位、第2632位～第2651位、第2633位～第2652位、第2634位～第2653位、第2635位～第2654位、第2636位～第2655位、第2637位～第2656位、第2638位～第2657位、第2639位～第2658位、第2640位～第2659位、第2641位～第2660位、第2642位～第2661位、第2643位～第2662位、第2644位～第2663位、第2645位～第2664位、第2646位～第2665位、第2647位～第2666位、第2648位～第2667位、第2649位～第2668位、第2663位～第2682位、第2672位～第2691位、第2673位～第2692位、第2674位～第2693位、第2675位～第2694位、第2676位～第2695位、第2677位～第2696位、第2678位～第2697位、第2679位～第2698位、第2680位～第2699位、第2681位～第2700位、第2682位～第2701位、第2683位～第2702位、第2684位～第2703位、第2685位～第2704位、第2686位～第2705位、第2687位～第2706位、第2688位～第2707位、第2689位～第2708位、第2690位～第2709位、第2691位～第2710位、第2692位～第2711位、第2693位～第2712位、第2694位～第2713位、第2695位～第2714位、第2696位～第2715位、第2697位～第2716位、第2698位～第2717位、第2699位～第2718位、第2700位～第2719位、第2701位～第2720位、第2702位～第2721位、第2703位～第2722位、第2704位～第2723位、第2705位～第2724位、第2706位～第2725位、第2707位～第2726位、第2708位～第2727位、第2709位～第2728位、第2710位～第2729位、第2711位～第2730位、第2712位～第2731位、第2713位～第2732位、第2714位～第2733位、第2715位～第2734位、第2716位～第2735位、第2717位～第2736位、第2718位～第2737位、第2719位～第2738位、第2720位～第2739位、第2721位～第2740位、第2722位～第2741位、第2723位～第2742位、第2724位～第2743位、第2725位～第2744位、第2726位～第2745位、第2727位～第2746位、第2728位～第2747位、第2729位～第2748位、第2730位～第2749位、第2731位～第2750位、第2732位～第2751位、第2733位～第2752位、第2738位～第2757位、第2775位～第2794位、第2790位～第2809位、第2826位～第2845位、第2827位～第2846位、第2828位～第2847位、第2829位～第2848位、第2830位～第2849位、第2831位～第2850位、第2832位～第2851位、第2833位～第2852位、第2834位～第2853位、第2835位～第2854位、第2836位～第2855位、第2837位～第2856位、第2838位～第2857位、第2839位～第2858位、第2840位～第2859位、第2841位～第2860位、第2842位～第2861位、第2843位～第2862位、第2844位～第2863位、第2847位～第2866位、第2959位～第2978位、第2962位～第2981位、第2963位～第2982位、第3032位～第3051位、第3052位～第3071位、第3136位～第3155位、第3168位～第3187位、第3188位～第3207位、第3232位～第3251位、第3251位～第3270位、第3298位～第3317位、第3302位～第3321位、第3303位～第3322位、第3304位～第3323位、第3305位～第3324位、第3306位～第3325位、第3307位～第3326位、第3308位～第3327位、第3309位～第3328位、第3310位～第3329位、第3311位～第3330位、第3312位～第3331位、第3313位～第3332位、第3314位～第3333位、第3315位～第3334位、第3316位～第3335位、第3317位～第3336位、第3318位～第3337位、第3319位～第3338位、第3320位～第3339位、第3321位～第3340位、第3322位～第3341位、第3323位～第3342位、第3324位～第3343位、第3325位～第3344位、第3408位～第3427位、第3563位～第3582位、第3590位～第3609位、第3608位～第3627位、第3617位～第3636位、第3618位～第3637位、第3619位～第3638位、第3620位～第3639位、第3621位～第3640位、第3622位～第3641位、第3623位～第3642位、第3624位～第3643位、第3625位～第3644位、第3626位～第3645位、第3627位～第3646位、第3628位～第3647位、第3629位～第3648位、第3630位～第3649位、第3631位～第3650位、第3632位～第3651位、第3633位～第3652位、第3634位～第3653位、第3635位～第3654位、第3636位～第3655位、第3637位～第3656位、第3638位～第3657位、第3639位～第3658位、第3640位～第3659位、第3641位～第3660位、第3642位～第3661位、第3643位～第3662位、第3644位～第3663位、第3645位～第3664位、第3646位～第3665位、第3647位～第3666位、第3648位～第3667位、第3649位～第3668位、第3650位～第3669位、第3651位～第3670位、第3652位～第3671位、第3653位～第3672位、第3654位～第3673位、第3671位～第3690位、第3672位～第3691位、第3673位～第3692位、第3674位～第3693位、第3675位～第3694位、第3676位～第3695位、第3677位～第3696位、第3678位～第3697位、第3679位～第3698位、第3680位～第3699位、第3681位～第3700位、第3682位～第3701位、第3683位～第3702位、第3684位～第3703位、第3685位～第3704位、第3686位～第3705位、第3687位～第3706位、第3688位～第3707位、第3689位～第3708位、第3690位～第3709位、第3691位～第3710位、第3692位～第3711位、第3693位～第3712位、第3694位～第3713位、第3695位～第3714位、第3696位～第3715位、第3697位～第3716位、第3698位～第3717位、第3699位～第3718位、第3700位～第3719位、第3701位～第3720位、第3702位～第3721位、第3703位～第3722位、第3704位～第3723位、第3705位～第3724位、第3706位～第3725位、第3707位～第3726位、第3708位～第3727位、第3709位～第3728位、第3739位～第3758位、第3740位～第3759位、第3741位～第3760位、第3742位～第3761位、第3743位～第3762位、第3744位～第3763位、第3745位～第3764位、第3750位～第3769位、第3877位～第3896位、第3949位～第3968位、第3964位～第3983位、第3965位～第3984位、第3966位～第3985位、第3967位～第3986位、第3968位～第3987位、第3969位～第3988位、第3970位～第3989位、第3971位～第3990位、第3972位～第3991位、第3973位～第3992位、第3974位～第3993位、第3975位～第3994位、第3976位～第3995位、第3977位～第3996位、第3978位～第3997位、第3979位～第3998位、第3980位～第3999位、第3981位～第4000位、第3982位～第4001位、第3983位～第4002位、第3984位～第4003位、第3985位～第4004位、第3986位～第4005位、第3987位～第4006位、第3988位～第4007位、第3989位～第4008位、第3990位～第4009位、第3991位～第4010位、第3992位～第4011位、第3993位～第4012位、第3994位～第4013位、第3995位～第4014位、第3996位～第4015位、第3997位～第4016位、第3998位～第4017位、第3999位～第4018位、第4011位～第4030位、第4170位～第4189位、第4173位～第4192位、第4176位～第4195位、第4177位～第4196位、第4178位～第4197位、第4179位～第4198位、第4180位～第4199位、第4181位～第4200位、第4182位～第4201位、第4183位～第4202位、第4184位～第4203位、第4185位～第4204位、第4186位～第4205位、第4187位～第4206位、第4188位～第4207位、第4189位～第4208位、第4190位～第4209位、第4191位～第4210位、第4192位～第4211位、第4193位～第4212位、第4194位～第4213位、第4195位～第4214位、第4196位～第4215位、第4197位～第4216位、第4198位～第4217位、第4199位～第4218位、第4200位～第4219位、第4201位～第4220位、第4202位～第4221位、第4203位～第4222位、第4204位～第4223位、第4205位～第4224位和第4206位～第4225位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 416, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 422, 404 to 423, 405 to 424, 406 to 425, 407 to 426, 408 to 427, 409 to 430, 410 to 431, 411 to 432, 412 to 433, 413 to 434, 414 to 435, 415 to 436, 416 to 437, 417 to 438, 418 to 439, 5th to 424th, 406th to 425th, 407th to 426th, 408th to 427th, 413th to 432nd, 723rd to 742nd, 747th to 766th, 756th to 775th, 759th to 778th, 965th to 984th, 1127th to 1146th, 1148th to 1167th, 1151st to 1170th, 1154th to 1173rd, 1182nd to 1201st, 11 85th to 1204th, 1188th to 1207th, 1191st to 1210th, 1194th to 1213th, 1228th to 1247th, 1231st to 1250th, 1235th to 1254th, 1270th to 1289th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 1510th, 1493rd to 1512th, 1506th to 1518th 25th, 1517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1579th to 1598th, 1580th to 1599th, 1581st to 1600th, 1582nd to 1601st, 1583rd to 1602nd, 1584th to 1603rd, 1585th to 1604th, 1586th to 1605th, 1587th to 1606th, 1588th to 1608th 8th to 1607th, 1589th to 1608th, 1590th to 1609th, 1591st to 1610th, 1592nd to 1611th, 1593rd to 1612th, 1594th to 1613th, 1595th to 1614th, 1596th to 1615th, 1597th to 1616th, 1598th to 1617th, 1599th to 1618th, 1600th to 1619th, 1601st to 1620th 0th, 1602nd to 1621st, 1603rd to 1622nd, 1604th to 1623rd, 1605th to 1624th, 1607th to 1626th, 1610th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1889th, 1871st to 1890th, 1874th to 1893rd, 1877th 1896th, 1878th - 1897th, 1879th - 1898th, 1880th - 1899th, 1881st - 1900th, 1882nd - 1901st, 1883rd - 1902nd, 1884th - 1903rd, 1885th - 1904th, 1886th - 1905th, 1887th - 1906th, 1889th - 1908th, 1894th - 1913th, 2015th - 2034th 2086th to 2105th, 2093rd to 2112th, 2094th to 2113th, 2097th to 2116th, 2099th to 2118th, 2129th to 2148th, 2151st to 2170th, 2165th to 2184th, 2206th to 2225th, 2239th to 2258th, 2253rd to 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th 2336th, 2337th to 2356th, 2354th to 2373rd, 2387th to 2406th, 2598th to 2617th, 2613th to 2632nd, 2614th to 2633rd, 2615th to 2634th, 2616th to 2635th, 2617th to 2636th, 2618th to 2637th, 2619th to 2638th, 2620th to 2639th, 2621st to 2640th , 2622nd to 2641st, 2623rd to 2642nd, 2624th to 2643rd, 2625th to 2644th, 2626th to 2645th, 2627th to 2646th, 2628th to 2647th, 2629th to 2648th, 2630th to 2649th, 2631st to 2650th, 2632nd to 2651st, 2633rd to 2652nd, 2634th to 2653rd, 2635th to No. 2654, No. 2636-No. 2655, No. 2637-No. 2656, No. 2638-No. 2657, No. 2639-No. 2658, No. 2640-No. 2659, No. 2641-No. 2660, No. 2642-No. 2661, No. 2643-No. 2662, No. 2644-No. 2663, No. 2645-No. 2664, No. 2646-No. 2665, No. 2647-No. 2666, No. 2648-No. 2667, 2649th to 2668th, 2663rd to 2682nd, 2672nd to 2691st, 2673rd to 2692nd, 2674th to 2693rd, 2675th to 2694th, 2676th to 2695th, 2677th to 2696th, 2678th to 2697th, 2679th to 2698th, 2680th to 2699th, 2681st to 2700th, 2682nd to 2701st, 2683rd to 2704th 2702nd, 2684th to 2703rd, 2685th to 2704th, 2686th to 2705th, 2687th to 2706th, 2688th to 2707th, 2689th to 2708th, 2690th to 2709th, 2691st to 2710th, 2692nd to 2711th, 2693rd to 2712th, 2694th to 2713th, 2695th to 2714th, 2696th to 2715th, 2697th to 2716th, 2698th to 2717th, 2699th to 2718th, 2700th to 2719th, 2701st to 2720th, 2702nd to 2721st, 2703rd to 2722nd, 2704th to 2723rd, 2705th to 2724th, 2706th to 2725th, 2707th to 2726th, 2708th to 2727th, 2709th to 2728th, 2710th to 2711th 2729th, 2711th to 2730th, 2712th to 2731st, 2713th to 2732nd, 2714th to 2733rd, 2715th to 2734th, 2716th to 2735th, 2717th to 2736th, 2718th to 2737th, 2719th to 2738th, 2720th to 2739th, 2721st to 2740th, 2722nd to 2741st, 2723rd to 2742nd, 27 24th to 2743rd, 2725th to 2744th, 2726th to 2745th, 2727th to 2746th, 2728th to 2747th, 2729th to 2748th, 2730th to 2749th, 2731st to 2750th, 2732nd to 2751st, 2733rd to 2752nd, 2738th to 2757th, 2775th to 2794th, 2790th to 2809th, 2826th to 284 5th, 2827th to 2846th, 2828th to 2847th, 2829th to 2848th, 2830th to 2849th, 2831st to 2850th, 2832nd to 2851st, 2833rd to 2852nd, 2834th to 2853rd, 2835th to 2854th, 2836th to 2855th, 2837th to 2856th, 2838th to 2857th, 2839th to 2858th, 284 0th to 2859th, 2841th to 2860th, 2842th to 2861st, 2843th to 2862nd, 2844th to 2863rd, 2847th to 2866th, 2959th to 2978th, 2962nd to 2981st, 2963rd to 2982nd, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3155th, 3168th to 3187th, 3188th to 3207th 3232nd to 3251st, 3251st to 3270th, 3298th to 3317th, 3302nd to 3321st, 3303rd to 3322nd, 3304th to 3323rd, 3305th to 3324th, 3306th to 3325th, 3307th to 3326th, 3308th to 3327th, 3309th to 3328th, 3310th to 3329th, 3311th to 3330th, 3312th 3311th to 3331st, 3313th to 3332nd, 3314th to 3333rd, 3315th to 3334th, 3316th to 3335th, 3317th to 3336th, 3318th to 3337th, 3319th to 3338th, 3320th to 3339th, 3321st to 3340th, 3322nd to 3341st, 3323rd to 3342nd, 3324th to 3343rd, 3325th to 3344th , 3408th to 3427th, 3563rd to 3582nd, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3618th to 3637th, 3619th to 3638th, 3620th to 3639th, 3621st to 3640th, 3622nd to 3641st, 3623rd to 3642nd, 3624th to 3643rd, 3625th to 3644th, 3626th 3645th, 3647th to 3646th, 3648th to 3647th, 3649th to 3648th, 3630th to 3649th, 3631st to 3650th, 3632nd to 3651st, 3633rd to 3652nd, 3634th to 3653rd, 3635th to 3654th, 3636th to 3655th, 3637th to 3656th, 3638th to 3657th, 3639th to 3658th, 3640th to 3659th, 3641st to 3660th, 3642nd to 3661st, 3643rd to 3662nd, 3644th to 3663rd, 3645th to 3664th, 3646th to 3665th, 3647th to 3666th, 3648th to 3667th, 3649th to 3668th, 3650th to 3669th, 3651st to 3670th, 3652nd to 3671st, 3653rd to 3672nd, 3654th to 3673rd, 3671st to 3690th, 3672nd to 3691st, 3673rd to 3692nd, 3674th to 3693rd, 3675th to 3694th, 3676th to 3695th, 3677th to 3696th, 3678th to 3697th, 3679th to 3698th, 3680th to 3699th, 3681st to 3700th, 3682nd to 3701st, 3 3683rd to 3702nd, 3684th to 3703rd, 3685th to 3704th, 3686th to 3705th, 3687th to 3706th, 3688th to 3707th, 3689th to 3708th, 3690th to 3709th, 3691st to 3710th, 3692nd to 3711th, 3693rd to 3712th, 3694th to 3713th, 3695th to 3714th, 3696th to 3715th 715th, 3697th-3716th, 3698th-3717th, 3699th-3718th, 3700th-3719th, 3701st-3720th, 3702nd-3721st, 3703rd-3722nd, 3704th-3723rd, 3705th-3724th, 3706th-3725th, 3707th-3726th, 3708th-3727th, 3709th-3728th, 37 39th to 3758th, 3740th to 3759th, 3741st to 3760th, 3742nd to 3761st, 3743rd to 3762nd, 3744th to 3763rd, 3745th to 3764th, 3750th to 3769th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3965th to 3984th, 3966th to 3985th, 3967th to 3989th 86th, 3968th-3987th, 3969th-3988th, 3970th-3989th, 3971st-3990th, 3972nd-3991st, 3973rd-3992nd, 3974th-3993rd, 3975th-3994th, 3976th-3995th, 3977th-3996th, 3978th-3997th, 3979th-3998th, 3980th-3999th, 3981st-3980th 1st to 4000th, 3982nd to 4001st, 3983rd to 4002nd, 3984th to 4003rd, 3985th to 4004th, 3986th to 4005th, 3987th to 4006th, 3988th to 4007th, 3989th to 4008th, 3990th to 4009th, 3991st to 4010th, 3992nd to 4011th, 3993rd to 4012th, 3994th to 4013th 3rd, 3995th to 4014th, 3996th to 4015th, 3997th to 4016th, 3998th to 4017th, 3999th to 4018th, 4011th to 4030th, 4170th to 4189th, 4173rd to 4192nd, 4176th to 4195th, 4177th to 4196th, 4178th to 4197th, 4179th to 4198th, 4180th to 4199th, 4181st 4182nd to 4201st, 4183rd to 4202nd, 4184th to 4203rd, 4185th to 4204th, 4186th to 4205th, 4187th to 4206th, 4188th to 4207th, 4189th to 4208th, 4190th to 4209th, 4191st to 4210th, 4192nd to 4211th, 4193rd to 4212th, 4194th to 4213th , at least 15 consecutive bases in the target region in the group consisting of positions 4195 to 4214, 4196 to 4215, 4197 to 4216, 4198 to 4217, 4199 to 4218, 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224 and 4206 to 4225.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号1～6、8、9、11、14～24、26、29、31～60、66～67、73～75、79～82、86～89、92～111、115～136、138～145、147～158和160～464组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464;

(ii)在选自由序列号1～6、8、9、11、14～24、26、29、31～60、66～67、73～75、79～82、86～89、92～111、115～136、138～145、147～158和160～464组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158 and 160 to 464; or

(iii)相对于选自由序列号1～6、8、9、11、14～24、26、29、31～60、66～67、73～75、79～82、86～89、92～111、115～136、138～145、147～158和160～464组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464,

例如，(i)的碱基序列。For example, the base sequence of (i).

本说明书中，添加、缺失或置换1个或数个碱基而成的碱基序列中的数个是指2个、3个、4个、5个、6个、7个、8个、9个或10个。In the present specification, the number in the base sequence obtained by adding, deleting or substituting one or several bases means 2, 3, 4, 5, 6, 7, 8, 9 or 10 bases.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第398位～第427位、第723位～第742位、第747位～第766位、第1148位～第1167位、第1289位～第1308位、第1484位～第1564位、第1578位～第1624位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1877位～第1906位、第2093位～第2113位、第2151位～第2170位、第2206位～第2225位、第2239位～第2272位、第2287位～第2336位、第2337位～第2373位、第2387位～第2406位、第2613位～第2752位、第2775位～第2809位、第2826位～第2863位、第2962位～第2982位、第3032位～第3051位、第3052位～第3071位、第3168位～第3187位、第3232位～第3270位、第3302位～第3343位、第3408位～第3427位、第3590位～第3728位、第3739位～第3764位、第3877位～第3896位、第3949位～第4030位和第4177位～第4225位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 14 to 33, 34 to 53, 398 to 427, 723 to 742, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1513, 1687 to 1711, 1768 to 1830, 1847 to 1861, 1870 to 1871, 1911 to 2030, 2130 to 2141, 2151 to 2163, 2167 to 2174, 2186 to 2191, 2230 to 2291, 2291 to 2303, 2311 to 2313, 2321 to 2334, 2333 to 2345, 2346 to 2366, 2367 to 2377, 2381 to 2391, 2413 to 2435, 2477 to 2483, 2497 to 2503, 2598 to 2514 1564th, 1578th to 1624th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1906th, 2093rd to 2113th, 2151st to 2170th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2613th to 2752nd, 2775th to 2809th, 2826th to 2863rd, 2962nd to 2982nd, 3032nd to 3051st, 3052nd to 3071st, 3168th to At least 15 consecutive bases in the target region in the group consisting of positions 3187, 3232 to 3270, 3302 to 3343, 3408 to 3427, 3590 to 3728, 3739 to 3764, 3877 to 3896, 3949 to 4030 and 4177 to 4225.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第398位～第417位、第399位～第418位、第400位～第419位、第401位～第420位、第402位～第421位、第403位～第422位、第404位～第423位、第405位～第424位、第406位～第425位、第407位～第426位、第408位～第427位、第723位～第742位、第747位～第766位、第1148位～第1167位、第1289位～第1308位、第1484位～第1503位、第1488位～第1507位、第1491位～第1510位、第1493位～第1512位、第1506位～第1525位、第1517位～第1536位、第1531位～第1550位、第1545位～第1564位、第1578位～第1597位、第1579位～第1598位、第1580位～第1599位、第1581位～第1600位、第1582位～第1601位、第1583位～第1602位、第1584位～第1603位、第1585位～第1604位、第1586位～第1605位、第1587位～第1606位、第1588位～第1607位、第1589位～第1608位、第1590位～第1609位、第1591位～第1610位、第1592位～第1611位、第1593位～第1612位、第1594位～第1613位、第1595位～第1614位、第1596位～第1615位、第1597位～第1616位、第1598位～第1617位、第1599位～第1618位、第1600位～第1619位、第1601位～第1620位、第1602位～第1621位、第1603位～第1622位、第1604位～第1623位、第1605位～第1624位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1877位～第1896位、第1878位～第1897位、第1879位～第1898位、第1880位～第1899位、第1881位～第1900位、第1882位～第1901位、第1883位～第1902位、第1884位～第1903位、第1885位～第1904位、第1886位～第1905位、第1887位～第1906位、第2093位～第2112位、第2094位～第2113位、第2151位～第2170位、第2206位～第2225位、第2239位～第2258位、第2253位～第2272位、第2287位～第2306位、第2301位～第2320位、第2317位～第2336位、第2337位～第2356位、第2354位～第2373位、第2387位～第2406位、第2613位～第2632位、第2614位～第2633位、第2615位～第2634位、第2616位～第2635位、第2617位～第2636位、第2618位～第2637位、第2619位～第2638位、第2620位～第2639位、第2621位～第2640位、第2622位～第2641位、第2623位～第2642位、第2624位～第2643位、第2625位～第2644位、第2626位～第2645位、第2627位～第2646位、第2628位～第2647位、第2629位～第2648位、第2630位～第2649位、第2631位～第2650位、第2632位～第2651位、第2633位～第2652位、第2634位～第2653位、第2635位～第2654位、第2636位～第2655位、第2637位～第2656位、第2638位～第2657位、第2639位～第2658位、第2640位～第2659位、第2641位～第2660位、第2642位～第2661位、第2643位～第2662位、第2644位～第2663位、第2645位～第2664位、第2646位～第2665位、第2647位～第2666位、第2648位～第2667位、第2649位～第2668位、第2663位～第2682位、第2672位～第2691位、第2673位～第2692位、第2674位～第2693位、第2675位～第2694位、第2676位～第2695位、第2677位～第2696位、第2678位～第2697位、第2679位～第2698位、第2680位～第2699位、第2681位～第2700位、第2682位～第2701位、第2683位～第2702位、第2684位～第2703位、第2685位～第2704位、第2686位～第2705位、第2687位～第2706位、第2688位～第2707位、第2689位～第2708位、第2690位～第2709位、第2691位～第2710位、第2692位～第2711位、第2693位～第2712位、第2694位～第2713位、第2695位～第2714位、第2696位～第2715位、第2697位～第2716位、第2698位～第2717位、第2699位～第2718位、第2700位～第2719位、第2701位～第2720位、第2702位～第2721位、第2703位～第2722位、第2704位～第2723位、第2705位～第2724位、第2706位～第2725位、第2707位～第2726位、第2708位～第2727位、第2709位～第2728位、第2710位～第2729位、第2711位～第2730位、第2712位～第2731位、第2713位～第2732位、第2714位～第2733位、第2715位～第2734位、第2716位～第2735位、第2717位～第2736位、第2718位～第2737位、第2719位～第2738位、第2720位～第2739位、第2721位～第2740位、第2722位～第2741位、第2723位～第2742位、第2724位～第2743位、第2725位～第2744位、第2726位～第2745位、第2727位～第2746位、第2728位～第2747位、第2729位～第2748位、第2730位～第2749位、第2731位～第2750位、第2732位～第2751位、第2733位～第2752位、第2775位～第2794位、第2790位～第2809位、第2826位～第2845位、第2827位～第2846位、第2828位～第2847位、第2829位～第2848位、第2830位～第2849位、第2831位～第2850位、第2832位～第2851位、第2833位～第2852位、第2834位～第2853位、第2835位～第2854位、第2836位～第2855位、第2837位～第2856位、第2838位～第2857位、第2839位～第2858位、第2840位～第2859位、第2841位～第2860位、第2842位～第2861位、第2843位～第2862位、第2844位～第2863位、第2962位～第2981位、第2963位～第2982位、第3032位～第3051位、第3052位～第3071位、第3168位～第3187位、第3232位～第3251位、第3251位～第3270位、第3302位～第3321位、第3303位～第3322位、第3304位～第3323位、第3305位～第3324位、第3306位～第3325位、第3307位～第3326位、第3308位～第3327位、第3309位～第3328位、第3310位～第3329位、第3311位～第3330位、第3312位～第3331位、第3313位～第3332位、第3314位～第3333位、第3315位～第3334位、第3316位～第3335位、第3317位～第3336位、第3318位～第3337位、第3319位～第3338位、第3320位～第3339位、第3321位～第3340位、第3322位～第3341位、第3323位～第3342位、第3324位～第3343位、第3408位～第3427位、第3590位～第3609位、第3608位～第3627位、第3617位～第3636位、第3618位～第3637位、第3619位～第3638位、第3620位～第3639位、第3621位～第3640位、第3622位～第3641位、第3623位～第3642位、第3624位～第3643位、第3625位～第3644位、第3626位～第3645位、第3627位～第3646位、第3628位～第3647位、第3629位～第3648位、第3630位～第3649位、第3631位～第3650位、第3632位～第3651位、第3633位～第3652位、第3634位～第3653位、第3635位～第3654位、第3636位～第3655位、第3637位～第3656位、第3638位～第3657位、第3639位～第3658位、第3640位～第3659位、第3641位～第3660位、第3642位～第3661位、第3643位～第3662位、第3644位～第3663位、第3645位～第3664位、第3646位～第3665位、第3647位～第3666位、第3648位～第3667位、第3649位～第3668位、第3650位～第3669位、第3651位～第3670位、第3652位～第3671位、第3653位～第3672位、第3654位～第3673位、第3671位～第3690位、第3672位～第3691位、第3673位～第3692位、第3674位～第3693位、第3675位～第3694位、第3676位～第3695位、第3677位～第3696位、第3678位～第3697位、第3679位～第3698位、第3680位～第3699位、第3681位～第3700位、第3682位～第3701位、第3683位～第3702位、第3684位～第3703位、第3685位～第3704位、第3686位～第3705位、第3687位～第3706位、第3688位～第3707位、第3689位～第3708位、第3690位～第3709位、第3691位～第3710位、第3692位～第3711位、第3693位～第3712位、第3694位～第3713位、第3695位～第3714位、第3696位～第3715位、第3697位～第3716位、第3698位～第3717位、第3699位～第3718位、第3700位～第3719位、第3701位～第3720位、第3702位～第3721位、第3703位～第3722位、第3704位～第3723位、第3705位～第3724位、第3706位～第3725位、第3707位～第3726位、第3708位～第3727位、第3709位～第3728位、第3739位～第3758位、第3740位～第3759位、第3741位～第3760位、第3742位～第3761位、第3743位～第3762位、第3744位～第3763位、第3745位～第3764位、第3877位～第3896位、第3949位～第3968位、第3964位～第3983位、第3965位～第3984位、第3966位～第3985位、第3967位～第3986位、第3968位～第3987位、第3969位～第3988位、第3970位～第3989位、第3971位～第3990位、第3972位～第3991位、第3973位～第3992位、第3974位～第3993位、第3975位～第3994位、第3976位～第3995位、第3977位～第3996位、第3978位～第3997位、第3979位～第3998位、第3980位～第3999位、第3981位～第4000位、第3982位～第4001位、第3983位～第4002位、第3984位～第4003位、第3985位～第4004位、第3986位～第4005位、第3987位～第4006位、第3988位～第4007位、第3989位～第4008位、第3990位～第4009位、第3991位～第4010位、第3992位～第4011位、第3993位～第4012位、第3994位～第4013位、第3995位～第4014位、第3996位～第4015位、第3997位～第4016位、第3998位～第4017位、第3999位～第4018位、第4011位～第4030位、第4177位～第4196位、第4178位～第4197位、第4179位～第4198位、第4180位～第4199位、第4181位～第4200位、第4182位～第4201位、第4183位～第4202位、第4184位～第4203位、第4185位～第4204位、第4186位～第4205位、第4187位～第4206位、第4188位～第4207位、第4189位～第4208位、第4190位～第4209位、第4191位～第4210位、第4192位～第4211位、第4193位～第4212位、第4194位～第4213位、第4195位～第4214位、第4196位～第4215位、第4197位～第4216位、第4198位～第4217位、第4199位～第4218位、第4200位～第4219位、第4201位～第4220位、第4202位～第4221位、第4203位～第4222位、第4204位～第4223位、第4205位～第4224位和第4206位～第4225位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 14 to 33, 34 to 53, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 422, 404 to 423, 405 to 424, 406 to 425 of the base sequence selected from the group consisting of positions 14 to 33, 34 to 53, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 422, 404 to 423, 405 to 424, 406 to 425th, 407th to 426th, 408th to 427th, 723rd to 742nd, 747th to 766th, 1148th to 1167th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 1510th, 1493rd to 1512th, 1506th to 1525th, 1517th to 1536th, 153 1st to 1550th, 1545th to 1564th, 1578th to 1597th, 1579th to 1598th, 1580th to 1599th, 1581st to 1600th, 1582nd to 1601st, 1583rd to 1602nd, 1584th to 1603rd, 1585th to 1604th, 1586th to 1605th, 1587th to 1606th, 1588th 1590-1609, 1591-1610, 1592-1611, 1593-1612, 1594-1613, 1595-1614, 1596-1615, 1597-1616, 1598-1617, 1599-1618, 1600-1 619th, 1601st to 1620th, 1602nd to 1621st, 1603rd to 1622nd, 1604th to 1623rd, 1605th to 1624th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1896th, 1878th to 1897th, 1879th to 1898th 8th, 1880th to 1899th, 1881st to 1900th, 1882nd to 1901st, 1883rd to 1902nd, 1884th to 1903rd, 1885th to 1904th, 1886th to 1905th, 1887th to 1906th, 2093rd to 2112th, 2094th to 2113th, 2151st to 2170th, 2206th to 2225th, 2239th to 2258th, 2253rd to 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th to 2336th, 2337th to 2356th, 2354th to 2373rd, 2387th to 2406th, 2613th to 2632nd, 2614th to 2633rd, 2615th to 2634th, 2616th to 2635th, 2 617th to 2636th, 2618th to 2637th, 2619th to 2638th, 2620th to 2639th, 2621st to 2640th, 2622nd to 2641st, 2623rd to 2642nd, 2624th to 2643rd, 2625th to 2644th, 2626th to 2645th, 2627th to 2646th, 2628th to 2647th, 2629th 2640th to 2649th, 2641st to 2650th, 2642nd to 2651st, 2643rd to 2652nd, 2644th to 2653rd, 2645th to 2654th, 2646th to 2655th, 2647th to 2656th, 2648th to 2657th, 2649th to 2658th, 2640th to 2659th, 2641st to 2660th, 2642nd to 2661st, 2643rd to 2662nd, 2644th to 2663rd, 2645th to 2664th, 2646th to 2665th, 2647th to 2666th, 2648th to 2667th, 2649th to 2668th, 2663rd to 2682nd, 2672nd to 2691st, 2673rd to 2692nd, 2674th to 2693rd 2675th to 2694th, 2676th to 2695th, 2677th to 2696th, 2678th to 2697th, 2679th to 2698th, 2680th to 2699th, 2681st to 2700th, 2682nd to 2701st, 2683rd to 2702nd, 2684th to 2703rd, 2685th to 2704th, 2686th to 270 5th, 2687th to 2706th, 2688th to 2707th, 2689th to 2708th, 2690th to 2709th, 2691st to 2710th, 2692nd to 2711th, 2693rd to 2712th, 2694th to 2713th, 2695th to 2714th, 2696th to 2715th, 2697th to 2716th, 2698th to 2717th, 2699th to 2718th, 2700th to 2719th, 2701st to 2720th, 2702nd to 2721st, 2703rd to 2722nd, 2704th to 2723rd, 2705th to 2724th, 2706th to 2725th, 2707th to 2726th, 2708th to 2727th, 2709th to 2728th, 2710th to 2729th, 2711th to 2712th 711th to 2730th, 2712th to 2731st, 2713th to 2732nd, 2714th to 2733rd, 2715th to 2734th, 2716th to 2735th, 2717th to 2736th, 2718th to 2737th, 2719th to 2738th, 2720th to 2739th, 2721st to 2740th, 2722nd to 2741st, 2723rd 2742nd, 2744th to 2743rd, 2725th to 2744th, 2726th to 2745th, 2727th to 2746th, 2728th to 2747th, 2729th to 2748th, 2730th to 2749th, 2731st to 2750th, 2732nd to 2751st, 2733rd to 2752nd, 2775th to 2794th, 2790th to 2809th, 2826th to 2845th, 2827th to 2846th, 2828th to 2847th, 2829th to 2848th, 2830th to 2849th, 2831st to 2850th, 2832nd to 2851st, 2833rd to 2852nd, 2834th to 2853rd, 2835th to 2854th, 2836th to 2855th, 2837th to 2858th 56th, 2838th to 2857th, 2839th to 2858th, 2840th to 2859th, 2841st to 2860th, 2842nd to 2861st, 2843rd to 2862nd, 2844th to 2863rd, 2962nd to 2981st, 2963rd to 2982nd, 3032nd to 3051st, 3052nd to 3071st, 3168th to 3187th 3232nd to 3251st, 3251st to 3270th, 3302nd to 3321st, 3303rd to 3322nd, 3304th to 3323rd, 3305th to 3324th, 3306th to 3325th, 3307th to 3326th, 3308th to 3327th, 3309th to 3328th, 3310th to 3329th, 3311th to 3330th, 3312th to 3331st, 3313th to 3332nd, 3314th to 3333rd, 3315th to 3334th, 3316th to 3335th, 3317th to 3336th, 3318th to 3337th, 3319th to 3338th, 3320th to 3329th, 3321st to 3340th, 3322nd to 3341st, 3323rd to 3342nd, 3343rd to 3344th 324th to 3343rd, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3618th to 3637th, 3619th to 3638th, 3620th to 3639th, 3621st to 3640th, 3622nd to 3641st, 3623rd to 3642nd, 3624th to 3643rd, 3625th 3644th, 3626th to 3645th, 3627th to 3646th, 3628th to 3647th, 3629th to 3648th, 3630th to 3649th, 3631st to 3650th, 3632nd to 3651st, 3633rd to 3652nd, 3634th to 3653rd, 3635th to 3654th, 3636th to 3655th, 3637th to 3656th, 3638th-3657th, 3639th-3658th, 3640th-3659th, 3641st-3660th, 3642nd-3661st, 3643rd-3662nd, 3644th-3663rd, 3645th-3664th, 3646th-3665th, 3647th-3666th, 3648th-3667th, 3649th-3650th 68th, 3650th to 3669th, 3651st to 3670th, 3652nd to 3671st, 3653rd to 3672nd, 3654th to 3673rd, 3671st to 3690th, 3672nd to 3691st, 3673rd to 3692nd, 3674th to 3693rd, 3675th to 3694th, 3676th to 3695th, 3677th to 3696th 3678th to 3697th, 3679th to 3698th, 3680th to 3699th, 3681st to 3700th, 3682nd to 3701st, 3683rd to 3702nd, 3684th to 3703rd, 3685th to 3704th, 3686th to 3705th, 3687th to 3706th, 3688th to 3707th, 3689th to 3708th, 3690th to 3709th, 3691st to 3710th, 3692nd to 3711th, 3693rd to 3712th, 3694th to 3713th, 3695th to 3714th, 3696th to 3715th, 3697th to 3716th, 3698th to 3717th, 3699th to 3718th, 3700th to 3719th, 3701st to 3720th, 37 02nd to 3721st, 3703rd to 3722nd, 3704th to 3723rd, 3705th to 3724th, 3706th to 3725th, 3707th to 3726th, 3708th to 3727th, 3709th to 3728th, 3739th to 3758th, 3740th to 3759th, 3741st to 3760th, 3742nd to 3761st, 3743rd 3762nd, 3744th to 3763rd, 3745th to 3764th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3965th to 3984th, 3966th to 3985th, 3967th to 3986th, 3968th to 3987th, 3969th to 3988th, 3970th to 3989th, 3971st to 3990th, 3972nd to 3991st, 3973rd to 3992nd, 3974th to 3993rd, 3975th to 3994th, 3976th to 3995th, 3977th to 3996th, 3978th to 3997th, 3979th to 3998th, 3980th to 3999th, 3981st to 4000th, 3982nd to 4001st, 3983rd to 4000th 2nd, 3984th to 4003rd, 3985th to 4004th, 3986th to 4005th, 3987th to 4006th, 3988th to 4007th, 3989th to 4008th, 3990th to 4009th, 3991st to 4010th, 3992nd to 4011th, 3993rd to 4012th, 3994th to 4013th, 3995th to 4014th , 3996th to 4015th, 3997th to 4016th, 3998th to 4017th, 3999th to 4018th, 4011th to 4030th, 4177th to 4196th, 4178th to 4197th, 4179th to 4198th, 4180th to 4199th, 4181st to 4200th, 4182nd to 4201st, 4183rd to 4202nd, 4 184th to 4203rd, 4185th to 4204th, 4186th to 4205th, 4187th to 4206th, 4188th to 4207th, 4189th to 4208th, 4190th to 4209th, 4191st to 4210th, 4192nd to 4211th, 4193rd to 4212th, 4194th to 4213th, 4195th to 4214th, 4196th to 4215th At least 15 consecutive bases in the target region in the group consisting of positions 6 to 4215, 4197 to 4216, 4198 to 4217, 4199 to 4218, 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224 and 4206 to 4225.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号1、5、6、14～24、31～35、37～40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163～464组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14-24, 31-35, 37-40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158, and 163-464;

(ii)在选自由序列号1、5、6、14～24、31～35、37～40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163～464组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163 to 464; or

(iii)相对于选自由序列号1、5、6、14～24、31～35、37～40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163～464组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163 to 464,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第54位～第73位、第148位～第167位、第397位～第432位、第747位～第778位、第965位～第984位、第1127位～第1146位、第1148位～第1173位、第1182位～第1213位、第1228位～第1254位、第1270位～第1308位、第1484位～第1564位、第1578位～第1629位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1870位～第1913位、第2015位～第2034位、第2086位～第2118位、第2129位～第2148位、第2151位～第2170位、第2206位～第2225位、第2239位～第2272位、第2287位～第2336位、第2337位～第2373位、第2387位～第2406位、第2598位～第2632位、第2633位～第2668位、第2672位～第2691位、第2699位～第2757位、第2775位～第2809位、第2826位～第2866位、第2959位～第2978位、第3032位～第3051位、第3052位～第3071位、第3136位～第3155位、第3168位～第3187位、第3188位～第3207位、第3232位～第3270位、第3298位～第3317位、第3325位～第3344位、第3408位～第3427位、第3590位～第3690位、第3691位～第3728位、第3739位～第3769位、第3877位～第3896位、第3949位～第3983位、第3984位～第4030位和第4170位～第4198位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 432, 747 to 778, 965 to 984, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1228 to 1254, 1270 to 1284, 1367 to 1391, 1404 to 1513, 1415 to 1524, 1430 to 1536, 1447 to 1547, 1450 to 1551, 1461 to 1563, 1471 to 1571, 1482 to 1581, 1490 to 1591, 1592 to 1603, 1614 to 1615, 1616 to 1624, 1635 to 1636, 1640 to 1653, 1654 to 1664, 1675 to 1676, 1680 to 1691, 1718 to 1725 1308th, 1484th to 1564th, 1578th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1913th, 2015th to 2034th, 2086th to 2118th, 2129th to 2148th, 2151st to 2170th, 2206th to 2225th, 2239th to 2272nd, 22 87th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2598th to 2632nd, 2633rd to 2668th, 2672nd to 2691st, 2699th to 2757th, 2775th to 2809th, 2826th to 2866th, 2959th to 2978th, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3155th, 3168th to 3187th , 3188th to 3207th, 3232nd to 3270th, 3298th to 3317th, 3325th to 3344th, 3408th to 3427th, 3590th to 3690th, 3691st to 3728th, 3739th to 3769th, 3877th to 3896th, 3949th to 3983rd, 3984th to 4030th and 4170th to 4198th.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第54位～第73位、第148位～第167位、第397位～第416位、第413位～第432位、第747位～第766位、第756位～第775位、第759位～第778位、第965位～第984位、第1127位～第1146位、第1148位～第1167位、第1151位～第1170位、第1154位～第1173位、第1182位～第1201位、第1185位～第1204位、第1188位～第1207位、第1191位～第1210位、第1194位～第1213位、第1228位～第1247位、第1231位～第1250位、第1235位～第1254位、第1270位～第1289位、第1289位～第1308位、第1484位～第1503位、第1488位～第1507位、第1491位～第1510位、第1493位～第1512位、第1506位～第1525位、第1517位～第1536位、第1531位～第1550位、第1545位～第1564位、第1578位～第1597位、第1586位～第1605位、第1589位～第1608位、第1592位～第1611位、第1595位～第1614位、第1598位～第1617位、第1601位～第1620位、第1604位～第1623位、第1607位～第1626位、第1610位～第1629位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1870位～第1889位、第1871位～第1890位、第1874位～第1893位、第1877位～第1896位、第1880位～第1899位、第1883位～第1902位、第1886位～第1905位、第1889位～第1908位、第1894位～第1913位、第2015位～第2034位、第2086位～第2105位、第2097位～第2116位、第2099位～第2118位、第2129位～第2148位、第2151位～第2170位、第2206位～第2225位、第2239位～第2258位、第2253位～第2272位、第2287位～第2306位、第2301位～第2320位、第2317位～第2336位、第2337位～第2356位、第2354位～第2373位、第2387位～第2406位、第2598位～第2617位、第2613位～第2632位、第2633位～第2652位、第2649位～第2668位、第2672位～第2691位、第2699位～第2718位、第2702位～第2721位、第2705位～第2724位、第2708位～第2727位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2720位～第2739位、第2723位～第2742位、第2726位～第2745位、第2729位～第2748位、第2738位～第2757位、第2775位～第2794位、第2790位～第2809位、第2826位～第2845位、第2829位～第2848位、第2832位～第2851位、第2835位～第2854位、第2838位～第2857位、第2841位～第2860位、第2847位～第2866位、第2959位～第2978位、第3032位～第3051位、第3052位～第3071位、第3136位～第3155位、第3168位～第3187位、第3188位～第3207位、第3232位～第3251位、第3251位～第3270位、第3298位～第3317位、第3325位～第3344位、第3408位～第3427位、第3590位～第3609位、第3608位～第3627位、第3617位～第3636位、第3635位～第3654位、第3654位～第3673位、第3671位～第3690位、第3691位～第3710位、第3709位～第3728位、第3739位～第3758位、第3750位～第3769位、第3877位～第3896位、第3949位～第3968位、第3964位～第3983位、第3984位～第4003位、第3999位～第4018位、第4011位～第4030位、第4170位～第4189位、第4173位～第4192位、第4176位～第4195位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 416, 413 to 432, 747 to 766, 756 to 775, 759 to 778, 965 to 984, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1173, 1182 to 1184, 201st, 1185th to 1204th, 1188th to 1207th, 1191st to 1210th, 1194th to 1213th, 1228th to 1247th, 1231st to 1250th, 1235th to 1254th, 1270th to 1289th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 1510th, 1493rd to 1512th, 1506th to 1525th, 1517th to 1536th, 1531st to 1550th , 1545th to 1564th, 1578th to 1597th, 1586th to 1605th, 1589th to 1608th, 1592nd to 1611th, 1595th to 1614th, 1598th to 1617th, 1601st to 1620th, 1604th to 1623rd, 1607th to 1626th, 1610th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1889th, 1 871st to 1890th, 1874th to 1893rd, 1877th to 1896th, 1880th to 1899th, 1883rd to 1902nd, 1886th to 1905th, 1889th to 1908th, 1894th to 1913th, 2015th to 2034th, 2086th to 2105th, 2097th to 2116th, 2099th to 2118th, 2129th to 2148th, 2151st to 2170th, 2206th to 2225th, 2239th to 2258th, 2253rd 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th to 2336th, 2337th to 2356th, 2354th to 2373rd, 2387th to 2406th, 2598th to 2617th, 2613th to 2632nd, 2633th to 2652nd, 2649th to 2668th, 2672nd to 2691st, 2699th to 2718th, 2702nd to 2721st, 2705th to 2724th, 2708th to 2727th, 2711th to 2 730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2723rd to 2742nd, 2726th to 2745th, 2729th to 2748th, 2738th to 2757th, 2775th to 2794th, 2790th to 2809th, 2826th to 2845th, 2829th to 2848th, 2832nd to 2851st, 2835th to 2854th, 2838th to 2857th, 2841st to 2860th, 2847th to 2866th , 2959th to 2978th, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3155th, 3168th to 3187th, 3188th to 3207th, 3232nd to 3251st, 3251st to 3270th, 3298th to 3317th, 3325th to 3344th, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3635th to 3654th, 3654th to 3673rd, 36 At least 15 consecutive bases in the target region in the group consisting of positions 371 to 3690, 3691 to 3710, 3709 to 3728, 3739 to 3758, 3750 to 3769, 3877 to 3896, 3949 to 3968, 3964 to 3983, 3984 to 4003, 3999 to 4018, 4011 to 4030, 4170 to 4189, 4173 to 4192, 4176 to 4195 and 4179 to 4198.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号1～4、6、8、9、11、14～24、26、29、31～37、39～50、52～60、66～67、73～75、79～82、86～89、92～111、115～118、120～136、138～145、147～158和160～163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163;

(ii)在选自由序列号1～4、6、8、9、11、14～24、26、29、31～37、39～50、52～60、66～67、73～75、79～82、86～89、92～111、115～118、120～136、138～145、147～158和160～163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158 and 160 to 163; or

(iii)相对于选自由序列号1～4、6、8、9、11、14～24、26、29、31～37、39～50、52～60、66～67、73～75、79～82、86～89、92～111、115～118、120～136、138～145、147～158和160～163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第747位～第766位、第1148位～第1167位、第1289位～第1308位、第1484位～第1564位、第1578位～第1623位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1877位～第1905位、第2151位～第2170位、第2206位～第2225位、第2239位～第2272位、第2287位～第2336位、第2337位～第2373位、第2387位～第2406位、第2613位～第2632位、第2633位～第2668位、第2672位～第2691位、第2699位～第2748位、第2775位～第2809位、第2826位～第2860位、第3032位～第3051位、第3052位～第3071位、第3168位～第3187位、第3232位～第3270位、第3408位～第3427位、第3590位～第3690位、第3691位～第3728位、第3739位～第3758位、第3877位～第3896位、第3949位～第3983位、第3984位～第4030位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 14 to 33, 34 to 53, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1564, 1578 to 1623, 1684 to 1730, 1767 to 1771, 1778 to 1791, 1800 to 1904, 1811 to 1913, 1814 to 1924, 1815 to 1930, 1816 to 1941, 1817 to 1951, 1818 to 1961, 1819 to 1973, 1824 to 1983, 1825 to 1984, 1826 to 1991, 1827 to 1993, 1828 to 1994, 1829 to 1995, 1830 to 1996 6th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1905th, 2151st to 2170th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th 2406th, 2613th - 2632nd, 2633rd - 2668th, 2672nd - 2691st, 2699th - 2748th, 2775th - 2809th, 2826th - 2860th, 3032nd - 3051st, 3052nd - 3071st, 3168th - 3187th, 3232nd At least 15 consecutive bases in the target region consisting of positions 31 to 3270, 3408 to 3427, 3590 to 3690, 3691 to 3728, 3739 to 3758, 3877 to 3896, 3949 to 3983, 3984 to 4030 and 4179 to 4198.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第14位～第33位、第34位～第53位、第747位～第766位、第1148位～第1167位、第1289位～第1308位、第1484位～第1503位、第1488位～第1507位、第1491位～第1510位、第1493位～第1512位、第1506位～第1525位、第1517位～第1536位、第1531位～第1550位、第1545位～第1564位、第1578位～第1597位、第1586位～第1605位、第1589位～第1608位、第1592位～第1611位、第1595位～第1614位、第1598位～第1617位、第1601位～第1620位、第1604位～第1623位、第1686位～第1705位、第1748位～第1767位、第1768位～第1787位、第1794位～第1813位、第1877位～第1896位、第1880位～第1899位、第1883位～第1902位、第1886位～第1905位、第2151位～第2170位、第2206位～第2225位、第2239位～第2258位、第2253位～第2272位、第2287位～第2306位、第2301位～第2320位、第2317位～第2336位、第2337位～第2356位、第2354位～第2373位、第2387位～第2406位、第2613位～第2632位、第2633位～第2652位、第2649位～第2668位、第2672位～第2691位、第2699位～第2718位、第2702位～第2721位、第2705位～第2724位、第2708位～第2727位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2720位～第2739位、第2723位～第2742位、第2726位～第2745位、第2729位～第2748位、第2775位～第2794位、第2790位～第2809位、第2826位～第2845位、第2829位～第2848位、第2832位～第2851位、第2835位～第2854位、第2838位～第2857位、第2841位～第2860位、第3032位～第3051位、第3052位～第3071位、第3168位～第3187位、第3232位～第3251位、第3251位～第3270位、第3408位～第3427位、第3590位～第3609位、第3608位～第3627位、第3617位～第3636位、第3635位～第3654位、第3654位～第3673位、第3671位～第3690位、第3691位～第3710位、第3709位～第3728位、第3739位～第3758位、第3877位～第3896位、第3949位～第3968位、第3964位～第3983位、第3984位～第4003位、第3999位～第4018位、第4011位～第4030位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 14 to 33, 34 to 53, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1492 to 1511, 1493 to 1512, 1494 to 1513, 1495 to 1514, 1496 to 1515, 1497 to 1516, 1498 to 1517, 1499 to 1520, 1491 to 1521, 1491 to 1523, 1497 to 1524, 1498 to 1525, 1499 to 1526, 1498 to 1527, 1499 to 1528, 1499 to 1529, 1491 to 1529, 1491 to 1529, 1491 to 1521 3rd to 1512th, 1506th to 1525th, 1517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1586th to 1605th, 1589th to 1608th, 1592nd to 1611th, 1595th to 1614th, 1598th to 1617th, 160 1st to 1620th, 1604th to 1623rd, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1896th, 1880th to 1899th, 1883rd to 1902nd, 1886th to 1905th, 2151st to 2170th, 220th 6th to 2225th, 2239th to 2258th, 2253rd to 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th to 2336th, 2337th to 2356th, 2354th to 2373rd, 2387th to 2406th, 2613th to 2632nd, 2633rd to 2652nd, 2649th 2668th, 2672nd - 2691st, 2699th - 2718th, 2702nd - 2721st, 2705th - 2724th, 2708th - 2727th, 2711th - 2730th, 2714th - 2733rd, 2717th - 2736th, 2720th - 2739th, 2723rd - 2742nd, 2726th 2745th, 2729th to 2748th, 2775th to 2794th, 2790th to 2809th, 2826th to 2845th, 2829th to 2848th, 2832nd to 2851st, 2835th to 2854th, 2838th to 2857th, 2841st to 2860th, 3032nd to 3051st, 3052nd 3071st, 3168th to 3187th, 3232nd to 3251st, 3251st to 3270th, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3635th to 3654th, 3654th to 3673rd, 3671st to 3690th, 3691st At least 15 consecutive bases in the target region of the group consisting of positions 3710 to 3710, 3709 to 3728, 3739 to 3758, 3877 to 3896, 3949 to 3968, 3964 to 3983, 3984 to 4003, 3999 to 4018, 4011 to 4030 and 4179 to 4198.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号1、6、14～24、31～35、37、39、40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14-24, 31-35, 37, 39, 40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158 and 163;

(ii)在选自由序列号1、6、14～24、31～35、37、39、40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163; or

(iii)相对于选自由序列号1、6、14～24、31～35、37、39、40、42～45、47～50、52～59、73、92～100、103、107～110、120～136、138～143、150～153、155～158和163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸选自：在按照本申请说明书的实施例记载的方法进行测定时，向A204细胞给药时的ATN-1基因表达量相对于给药阳性对照反义寡核苷酸OMe-6或NRH-71时的ATN-1基因表达量的比(平均值)在任一实施例中均为1.0以下的反义寡核苷酸。作为这样的反义寡核苷酸的例子，可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第397位～第416位、第759位～第778位、第1127位～第1146位、第1148位～第1173位、第1182位～第1213位、第1488位～第1525位、第1586位～第1629位、第1686位～第1705位、第1768位～第1787位、第1870位～第1908位、第2097位～第2118位、第2151位～第2170位、第2239位～第2258位、第2287位～第2306位、第2317位～第2336位、第2633位～第2652位、第2702位～第2745位、第2832位～第2866位、第2959位～第2978位、第3298位～第3317位、第3635位～第3654位、第3671位～第3690位、第3691位～第3710位、第3750位～第3983位、第3984位～第4003位和第4170位～第4198位组成的组中的靶区域中的至少15个连续的碱基。另外可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第397位～第416位、第759位～第778位、第1127位～第1146位、第1148位～第1167位、第1151位～第1170位、第1154位～第1173位、第1182位～第1201位、第1185位～第1204位、第1194位～第1213位、第1488位～第1507位、第1491位～第1510位、第1506位～第1525位、第1586位～第1605位、第1589位～第1608位、第1595位～第1614位、第1598位～第1617位、第1601位～第1620位、第1604位～第1623位、第1607位～第1626位、第1610位～第1629位、第1686位～第1705位、第1768位～第1787位、第1870位～第1889位、第1871位～第1890位、第1874位～第1893位、第1877位～第1896位、第1886位～第1905位、第1889位～第1908位、第2097位～第2116位、第2099位～第2118位、第2151位～第2170位、第2239位～第2258位、第2287位～第2306位、第2317位～第2336位、第2633位～第2652位、第2702位～第2721位、第2705位～第2724位、第2708位～第2727位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2720位～第2739位、第2726位～第2745位、第2832位～第2851位、第2835位～第2854位、第2841位～第2860位、第2847位～第2866位、第2959位～第2978位、第3298位～第3317位、第3635位～第3654位、第3671位～第3690位、第3691位～第3710位、第3750位～第3769位、第3964位～第3983位、第3984位～第4003位、第4170位～第4189位、第4173位～第4192位、第4176位～第4195位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is selected from: antisense oligonucleotides whose ratio (average value) of the ATN-1 gene expression level when administered to A204 cells relative to the ATN-1 gene expression level when the positive control antisense oligonucleotide OMe-6 or NRH-71 is administered is less than 1.0 in any of the embodiments when measured according to the method described in the examples of the specification of the present application. Examples of such antisense oligonucleotides include: an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 397 to 416, 759 to 778, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1488 to 1525, 1586 to 1629, 1686 to 1705, 1768 to 1787, 1870 to 1908, 2097 to 2118, 215 At least 15 consecutive bases in the target region in the group consisting of positions 1 to 2170, 2239 to 2258, 2287 to 2306, 2317 to 2336, 2633 to 2652, 2702 to 2745, 2832 to 2866, 2959 to 2978, 3298 to 3317, 3635 to 3654, 3671 to 3690, 3691 to 3710, 3750 to 3983, 3984 to 4003 and 4170 to 4198. Another example is an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 397 to 416, 759 to 778, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1173, 1182 to 1201, 1185 to 1204, 1194 to 1213, 1488 to 1507, 1491 to 1510, 1506 to 1525, 1 586th to 1605th, 1589th to 1608th, 1595th to 1614th, 1598th to 1617th, 1601st to 1620th, 1604th to 1623rd, 1607th to 1626th, 1610th to 1629th, 1686th to 1705th, 1768th to 1787th, 1870th to 1889th, 1871st to 1890th, 1874th to 1893rd, 1877th to 1896th, 1886th to 1905th, 1889th to 1908th, 209th 7th to 2116th, 2099th to 2118th, 2151st to 2170th, 2239th to 2258th, 2287th to 2306th, 2317th to 2336th, 2633rd to 2652nd, 2702nd to 2721st, 2705th to 2724th, 2708th to 2727th, 2711th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2726th to 2745th, 2832nd to 2851st, 2835th At least 15 consecutive bases in the target region in the group consisting of positions 1 to 2854, 2841 to 2860, 2847 to 2866, 2959 to 2978, 3298 to 3317, 3635 to 3654, 3671 to 3690, 3691 to 3710, 3750 to 3769, 3964 to 3983, 3984 to 4003, 4170 to 4189, 4173 to 4192, 4176 to 4195 and 4179 to 4198.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号9、11、16、17、22、31、60、67、73、74、75、79、80、92、95～107、110、111、116、117、120～122、126、128～134、136、140、141、143～145、148、151～154、156、157和160～163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95-107, 110, 111, 116, 117, 120-122, 126, 128-134, 136, 140, 141, 143-145, 148, 151-154, 156, 157, and 160-163;

(ii)在选自由序列号9、11、16、17、22、31、60、67、73、74、75、79、80、92、95～107、110、111、116、117、120～122、126、128～134、136、140、141、143～145、148、151～154、156、157和160～163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157 and 160 to 163; or

(iii)相对于选自由序列号9、11、16、17、22、31、60、67、73、74、75、79、80、92、95～107、110、111、116、117、120～122、126、128～134、136、140、141、143～145、148、151～154、156、157和160～163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157, and 160 to 163,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸选自：在按照本申请说明书的实施例记载的方法进行测定时，向A204细胞给药时的ATN-1基因表达量相对于给药阳性对照反义寡核苷酸OMe-6或NRH-71时的ATN-1基因表达量的比(平均值)在任一实施例中均为0.75以下的反义寡核苷酸。作为这样的反义寡核苷酸的例子，可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第397位～第416位、第1194位～第1213位、第1506位～第1525位、第1586位～第1626位、第1870位～第1896位、第2097位～第2116位、第2317位～第2336位、第2633位～第2652位、第2702位～第2739位、第2841位～第2978位、第3298位～第3317位、第3635位～第3654位、第3691位～第3710位、第3750位～第3769位、第3984位～第4003位和第4170位～第4198位组成的组中的靶区域中的至少15个连续的碱基。另外可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第397位～第416位、第1194位～第1213位、第1506位～第1525位、第1586位～第1605位、第1595位～第1614位、第1598位～第1617位、第1604位～第1623位、第1607位～第1626位、第1870位～第1889位、第1871位～第1890位、第1874位～第1893位、第1877位～第1896位、第2097位～第2116位、第2317位～第2336位、第2633位～第2652位、第2702位～第2721位、第2708位～第2727位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2720位～第2739位、第2841位～第2860位、第2959位～第2978位、第3298位～第3317位、第3635位～第3654位、第3691位～第3710位、第3750位～第3769位、第3984位～第4003位、第4170位～第4189位、第4173位～第4192位、第4176位～第4195位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is selected from: when measured according to the method described in the examples of the specification of the present application, the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells relative to the ATN-1 gene expression level when the positive control antisense oligonucleotide OMe-6 or NRH-71 is administered is 0.75 or less in any of the examples. As an example of such an antisense oligonucleotide, there can be listed: an antisense oligonucleotide composed of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 397 to 416, 1194 to 1213, 1506 to 1525, 1586 to 1626, 1870 to 1896, 2097 to 2116, 23 At least 15 consecutive bases in the target region in the group consisting of positions 17 to 2336, 2633 to 2652, 2702 to 2739, 2841 to 2978, 3298 to 3317, 3635 to 3654, 3691 to 3710, 3750 to 3769, 3984 to 4003 and 4170 to 4198. Another example is an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to a nucleic acid comprising: positions 397 to 416, 1194 to 1213, 1506 to 1525, 1586 to 1605, 1595 to 1614, 1598 to 1617, 1604 to 1623, 1607 to 1626, 1870 to 1889, 1871 to 1890, 1874 to 1893, 1877 to 1896, 2097 to 2116, 2317 to 2336, 2633 to 2643, 52nd, 2702nd to 2721st, 2708th to 2727th, 2711th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2841st to 2860th, 2959th to 2978th, 3298th to 3317th, At least 15 consecutive bases in the target region of the group consisting of positions 3635 to 3654, 3691 to 3710, 3750 to 3769, 3984 to 4003, 4170 to 4189, 4173 to 4192, 4176 to 4195 and 4179 to 4198.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号11、60、92、95、97、98、100、101、104～107、116、122、126、128、130～134、143、145、148、151、153、154、157和160～163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104-107, 116, 122, 126, 128, 130-134, 143, 145, 148, 151, 153, 154, 157, and 160-163;

(ii)在选自由序列号11、60、92、95、97、98、100、101、104～107、116、122、126、128、130～134、143、145、148、151、153、154、157和160～163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157 and 160 to 163; or

(iii)相对于选自由序列号11、60、92、95、97、98、100、101、104～107、116、122、126、128、130～134、143、145、148、151、153、154、157和160～163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157, and 160 to 163,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸选自：在按照本申请说明书的实施例记载的方法进行测定时，向A204细胞给药时的ATN-1基因表达量相对于给药阳性对照反义寡核苷酸OMe-6或NRH-71时的ATN-1基因表达量的比(平均值)在任一实施例中均为0.5以下的反义寡核苷酸。作为这样的反义寡核苷酸的例子，可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1598位～第1626位、第1870位～第1890位、第2097位～第2116位、第2711位～第2736位、第2841位～第2860位和第4170位～第4198位组成的组中的靶区域中的至少15个连续的碱基。另外可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1598位～第1617位、第1604位～第1623位、第1607位～第1626位、第1870位～第1889位、第1871位～第1890位、第2097位～第2116位、第2711位～第2730位、第2714位～第2733位、第2717位～第2736位、第2841位～第2860位、第4170位～第4189位、第4173位～第4192位和第4179位～第4198位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is selected from: when measured according to the method described in the examples of the specification of the present application, the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells relative to the ATN-1 gene expression level when the positive control antisense oligonucleotide OMe-6 or NRH-71 is administered is 0.5 or less in any of the examples. As an example of such an antisense oligonucleotide, there can be cited: an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises: at least 15 consecutive bases in the target region selected from the group consisting of positions 1598 to 1626, 1870 to 1890, 2097 to 2116, 2711 to 2736, 2841 to 2860, and 4170 to 4198 of the base sequence of SEQ ID NO: 471. Another example is an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises: at least 15 consecutive bases in a target region selected from the group consisting of positions 1598 to 1617, positions 1604 to 1623, positions 1607 to 1626, positions 1870 to 1889, positions 1871 to 1890, positions 2097 to 2116, positions 2711 to 2730, positions 2714 to 2733, positions 2717 to 2736, positions 2841 to 2860, positions 4170 to 4189, positions 4173 to 4192, and positions 4179 to 4198 of the base sequence of SEQ ID NO: 471.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号98、100、101、104、105、116、131～133、143、160、161和163组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161 and 163;

(ii)在选自由序列号98、100、101、104、105、116、131～133、143、160、161和163组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161 and 163; or

(iii)相对于选自由序列号98、100、101、104、105、116、131～133、143、160、161和163组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第400位～第425位、第1581位～第1624位、第1878位～第1898位、第2094位～第2113位、第2629位～第2656位、第2700位～第2741位、第2839位～第2863位、第2962位～第2981位、第3302位～第3325位、第3631位～第3658位、第3687位～第3714位、第3745位～第3764位、第3980位～第4007位、第4177位～第4199位和第4204位～第4223位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 400 to 425, 1581 to 1624, 1878 to 1898, 2094 to 2113, 2629 to 2656, 2700 to 2741, 2839 to 2947, 3061 to 3069, 3130 to 3141, 3291 to 3333, 3437 to 3567, 3610 to 3741, 3820 to 3869, 3911 to 3969, 4071 to 4131, 4132 to 4143, 4291 to 4334, 4352 to 4369, 4403 to 4535, 4544 to 4616, 4617 to 4627, 4718 to 4729, 4819 to 4910, 4921 to 4931, 4940 to 4953, 4954 to 4969, 4971 to 4983 At least 15 consecutive bases in the target region of the group consisting of positions 2863, 2962 to 2981, 3302 to 3325, 3631 to 3658, 3687 to 3714, 3745 to 3764, 3980 to 4007, 4177 to 4199 and 4204 to 4223.

一个实施方式中，本发明的反义寡核苷酸与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第400位～第419位、第403位～第422位、第406位～第425位、第1581位～第1600位、第1582位～第1601位、第1583位～第1602位、第1584位～第1603位、第1585位～第1604位、第1587位～第1606位、第1588位～第1607位、第1590位～第1609位、第1591位～第1610位、第1592位～第1611位、第1593位～第1612位、第1594位～第1613位、第1596位～第1615位、第1597位～第1616位、第1599位～第1618位、第1600位～第1619位、第1602位～第1621位、第1603位～第1622位、第1605位～第1624位、第1878位～第1897位、第1879位～第1898位、第2094位～第2113位、第2629位～第2648位、第2637位～第2656位、第2700位～第2719位、第2701位～第2720位、第2703位～第2722位、第2704位～第2723位、第2706位～第2725位、第2707位～第2726位、第2709位～第2728位、第2710位～第2729位、第2712位～第2731位、第2713位～第2732位、第2715位～第2734位、第2716位～第2735位、第2718位～第2737位、第2719位～第2738位、第2721位～第2740位、第2722位～第2741位、第2839位～第2858位、第2840位～第2859位、第2842位～第2861位、第2843位～第2862位、第2844位～第2863位、第2962位～第2981位、第3302位～第3321位、第3306位～第3325位、第3631位～第3650位、第3632位～第3651位、第3633位～第3652位、第3634位～第3653位、第3636位～第3655位、第3637位～第3656位、第3638位～第3657位、第3639位～第3658位、第3687位～第3706位、第3695位～第3714位、第3745位～第3764位、第3980位～第3999位、第3988位～第4007位、第4177位～第4196位、第4178位～第4197位、第4180位～第4199位和第4204位～第4223位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 400 to 419, 403 to 422, 406 to 425, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1590 to 1609, 1591 to 1610, 1592 to 1611, 1593 to 1612, 1594 to 1613, and 1595 to 1614 of the base sequence selected from the group consisting of positions 400 to 419, 403 to 422, 406 to 425, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1590 to 1609, 1596th to 1615th, 1597th to 1616th, 1599th to 1618th, 1600th to 1619th, 1602nd to 1621st, 1603rd to 1622nd, 1605th to 1624th, 1878th to 1897th, 1879th to 1898th, 2 2094th to 2113th, 2629th to 2648th, 2637th to 2656th, 2700th to 2719th, 2701st to 2720th, 2703rd to 2722nd, 2704th to 2723rd, 2706th to 2725th, 2707th to 2726th, 27 09th to 2728th, 2710th to 2729th, 2712th to 2731st, 2713th to 2732nd, 2715th to 2734th, 2716th to 2735th, 2718th to 2737th, 2719th to 2738th, 2721st to 2740th, 272 2nd to 2741st, 2839th to 2858th, 2840th to 2859th, 2842nd to 2861st, 2843rd to 2862nd, 2844th to 2863rd, 2962nd to 2981st, 3302nd to 3321st, 3306th to 3325th, 3631st 3650th, 3632nd to 3651st, 3633rd to 3652nd, 3634th to 3653rd, 3636th to 3655th, 3637th to 3656th, 3638th to 3657th, 3639th to 3658th, 3687th to 3706th, 3695th At least 15 consecutive bases in the target region consisting of positions 3714 to 3714, 3745 to 3764, 3980 to 3999, 3988 to 4007, 4177 to 4196, 4178 to 4197, 4180 to 4199 and 4204 to 4223.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号21、164～222、233、234和350～355组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355;

(ii)在选自由序列号21、164～222、233、234和350～355组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234 and 350 to 355; or

(iii)相对于选自由序列号21、164～222、233、234和350～355组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸为：在按照本申请说明书的实施例记载的方法进行测定时，向A204细胞给药时的ATN-1基因表达量相对于给药阳性对照反义寡核苷酸OMe-6或NRH-71时的ATN-1基因表达量的比(平均值)在任一实施例中均为1.0以下的反义寡核苷酸。作为这样的反义寡核苷酸的例子，可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第400位～第425位、第1581位～第1624位、第1878位～第1898位、第2637位～第2656位、第2700位～第2741位、第2839位～第2863位、第2962位～第2981位、第3302位～第3325位、第3631位～第3658位、第3687位～第3706位、第3745位～第3764位、第4177位～第4199位和第4204位～第4223位组成的组中的靶区域中的至少15个连续的碱基。另外可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第400位～第419位、第403位～第422位、第406位～第425位、第1581位～第1600位、第1582位～第1601位、第1583位～第1602位、第1584位～第1603位、第1585位～第1604位、第1587位～第1606位、第1588位～第1607位、第1591位～第1610位、第1592位～第1611位、第1593位～第1612位、第1594位～第1613位、第1596位～第1615位、第1597位～第1616位、第1600位～第1619位、第1602位～第1621位、第1603位～第1622位、第1605位～第1624位、第1878位～第1897位、第1879位～第1898位、第2637位～第2656位、第2700位～第2719位、第2701位～第2720位、第2703位～第2722位、第2704位～第2723位、第2706位～第2725位、第2707位～第2726位、第2709位～第2728位、第2710位～第2729位、第2712位～第2731位、第2713位～第2732位、第2715位～第2734位、第2716位～第2735位、第2718位～第2737位、第2719位～第2738位、第2721位～第2740位、第2722位～第2741位、第2839位～第2858位、第2840位～第2859位、第2842位～第2861位、第2843位～第2862位、第2844位～第2863位、第2962位～第2981位、第3302位～第3321位、第3306位～第3325位、第3631位～第3650位、第3632位～第3651位、第3633位～第3652位、第3634位～第3653位、第3636位～第3655位、第3637位～第3656位、第3638位～第3657位、第3639位～第3658位、第3687位～第3706位、第3745位～第3764位、第4177位～第4196位、第4178位～第4197位、第4180位～第4199位和第4204位～第4223位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is an antisense oligonucleotide wherein, when measured according to the method described in the examples of the present specification, the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells relative to the ATN-1 gene expression level when administered with the positive control antisense oligonucleotide OMe-6 or NRH-71 is less than 1.0 in any of the examples. As an example of such an antisense oligonucleotide, there can be mentioned: an antisense oligonucleotide composed of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises: at least 15 consecutive bases in a target region selected from the group consisting of positions 400 to 425, positions 1581 to 1624, positions 1878 to 1898, positions 2637 to 2656, positions 2700 to 2741, positions 2839 to 2863, positions 2962 to 2981, positions 3302 to 3325, positions 3631 to 3658, positions 3687 to 3706, positions 3745 to 3764, positions 4177 to 4199 and positions 4204 to 4223 of the base sequence of SEQ ID NO: 471. Another example is an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 400 to 419, 403 to 422, 406 to 425, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1591 to 1610, 1592 to 1611, 1593 to 161 2nd, 1594th to 1613th, 1596th to 1615th, 1597th to 1616th, 1600th to 1619th, 1602nd to 1621st, 1603rd to 1622nd, 1605th to 1624th, 1878th to 1897th, 1879th to 1898th, 2637th to 2656th, 2700th to 2719th, 2701st to 2720th, 2703rd to 2722nd, 2704th to 2723rd, 2706th to 2725th, 2707th to 2726th, 2709th 2728th, 2710th - 2729th, 2712th - 2731st, 2713th - 2732nd, 2715th - 2734th, 2716th - 2735th, 2718th - 2737th, 2719th - 2738th, 2721st - 2740th, 2722nd - 2741st, 2839th - 2858th, 2840th - 2859th, 2842nd - 2861st, 2843rd - 2862nd, 2844th - 2863rd, 2962nd - 2981st, 3302nd - 3321st , at least 15 consecutive bases in the target region in the group consisting of positions 3306 to 3325, 3631 to 3650, 3632 to 3651, 3633 to 3652, 3634 to 3653, 3636 to 3655, 3637 to 3656, 3638 to 3657, 3639 to 3658, 3687 to 3706, 3745 to 3764, 4177 to 4196, 4178 to 4197, 4180 to 4199 and 4204 to 4223.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号21、164～171、173～177、179～184、187～214、216、219～222、233～234和350～355组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355;

(ii)在选自由序列号21、164～171、173～177、179～184、187～214、216、219～222、233～234和350～355组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234 and 350 to 355; or

(iii)相对于选自由序列号21、164～171、173～177、179～184、187～214、216、219～222、233～234和350～355组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸为：在按照本申请说明书的实施例记载的方法进行测定时，向A204细胞给药时的ATN-1基因表达量相对于给药阳性对照反义寡核苷酸OMe-6或NRH-71时的ATN-1基因表达量的比(平均值)在任一实施例中均为0.75以下的反义寡核苷酸。作为这样的反义寡核苷酸的例子，可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1581位～第1624位、第2703位～第2740位、第3633位～第3655位和第4177位～第4199位组成的组中的靶区域中的至少15个连续的碱基。另外可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1581位～第1600位、第1582位～第1601位、第1584位～第1603位、第1585位～第1604位、第1587位～第1606位、第1588位～第1607位、第1594位～第1613位、第1596位～第1615位、第1597位～第1616位、第1602位～第1621位、第1603位～第1622位、第1605位～第1624位、第2703位～第2722位、第2707位～第2726位、第2709位～第2728位、第2710位～第2729位、第2712位～第2731位、第2713位～第2732位、第2715位～第2734位、第2716位～第2735位、第2718位～第2737位、第2719位～第2738位、第2721位～第2740位、第3633位～第3652位、第3634位～第3653位、第3636位～第3655位、第4177位～第4196位、第4178位～第4197位和第4180位～第4199位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is an antisense oligonucleotide wherein the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells relative to the ATN-1 gene expression level when administered with the positive control antisense oligonucleotide OMe-6 or NRH-71 is 0.75 or less in any of the embodiments. Examples of such antisense oligonucleotides include an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises at least 15 consecutive bases in a target region selected from the group consisting of positions 1581 to 1624, positions 2703 to 2740, positions 3633 to 3655, and positions 4177 to 4199 of the base sequence of SEQ ID NO: 471. Another example is an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 1581 to 1600, 1582 to 1601, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1594 to 1613, 1596 to 1615, 1597 to 1616, 1602 to 1621, 1603 to 1622, 1605 to 1624, 2703 to 2722, 2704 to 2723, 2705 to 2724, 2706 to 2725, 2707 to 2726, 2708 to 2727 At least 15 consecutive bases in the target region in the group consisting of positions 2707 to 2726, 2709 to 2728, 2710 to 2729, 2712 to 2731, 2713 to 2732, 2715 to 2734, 2716 to 2735, 2718 to 2737, 2719 to 2738, 2721 to 2740, 3633 to 3652, 3634 to 3653, 3636 to 3655, 4177 to 4196, 4178 to 4197 and 4180 to 4199.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号167～171、175～177、180～182、190、193～202、219～221、233和351～353组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353;

(ii)在选自由序列号167～171、175～177、180～182、190、193～202、219～221、233和351～353组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233 and 351 to 353; or

(iii)相对于选自由序列号167～171、175～177、180～182、190、193～202、219～221、233和351～353组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸为：在按照本申请说明书的实施例记载的方法进行测定时，向A204细胞给药时的ATN-1基因表达量相对于给药阳性对照反义寡核苷酸OMe-6或NRH-71时的ATN-1基因表达量的比(平均值)在任一实施例中均为0.5以下的反义寡核苷酸。作为这样的反义寡核苷酸的例子，可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1587位～第1616位、第2712位～第2735位和第4180位～第4199位组成的组中的靶区域中的至少15个连续的碱基。另外可列举：一种反义寡核苷酸，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第1587位～第1606位、第1597位～第1616位、第2712位～第2731位、第2716位～第2735位和第4180位～第4199位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the antisense oligonucleotide of the present invention is an antisense oligonucleotide wherein the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells relative to the ATN-1 gene expression level when administered with the positive control antisense oligonucleotide OMe-6 or NRH-71 is 0.5 or less in any of the embodiments. Examples of such antisense oligonucleotides include an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises at least 15 consecutive bases in a target region selected from the group consisting of positions 1587 to 1616, positions 2712 to 2735, and positions 4180 to 4199 of the base sequence of SEQ ID NO: 471. Also listed is: an antisense oligonucleotide consisting of 15 to 22 nucleotides and complementary to the following nucleic acid, wherein the nucleic acid comprises: at least 15 consecutive bases in a target region selected from the group consisting of positions 1587 to 1606, positions 1597 to 1616, positions 2712 to 2731, positions 2716 to 2735, and positions 4180 to 4199 of the base sequence of sequence number 471.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号170、177、196、199和221组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199 and 221;

(ii)在选自由序列号170、177、196、199和221组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199 and 221; or

(iii)相对于选自由序列号170、177、196、199和221组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a base sequence having a sequence identity of 90% or more to the base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199 and 221,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明涉及反义寡核苷酸或其药物上可接受的盐或者它们的水合物，其由15～22个核苷酸构成且与下述核酸互补，所述核酸包含：选自由序列号471的碱基序列的第468位～第487位、第474位～第493位、第583位～第602位、第586位～第605位、第619位～第638位、第770位～第789位、第774位～第793位、第775位～第794位、第778位～第797位、第804位～第823位、第851位～第870位、第1160位～第1179位、第1162位～第1181位、第1170位～第1189位、第1173位～第1192位、第1205位～第1224位、第1210位～第1229位、第1216位～第1235位、第1217位～第1236位、第1219位～第1238位、第1385位～第1404位、第1441位～第1460位、第1818位～第1837位、第1902位～第1921位、第1905位～第1924位、第1908位～第1927位、第1914位～第1933位、第1931位～第1950位、第2117位～第2136位、第2749位～第2768位、第3100位～第3119位和第4125位～第4144位组成的组中的靶区域中的至少15个连续的碱基。In one embodiment, the present invention relates to an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof, which is composed of 15 to 22 nucleotides and is complementary to the following nucleic acid, wherein the nucleic acid comprises: positions 468 to 487, 474 to 493, 583 to 602, 586 to 605, 619 to 638, 770 to 789, 774 to 793, 775 to 794, 778 to 797, 804 to 823, 851 to 870, 1160 to 1179, 1162 to 1181, 1170 to 1189, 1173 to 1184 of the base sequence selected from the group consisting of SEQ ID NO: 471. 1192nd, 1205th to 1224th, 1210th to 1229th, 1216th to 1235th, 1217th to 1236th, 1219th to 1238th, 1385th to 1404th, 1441st to 1460th, 1818th to 1837th, 1902nd to 1921st, At least 15 consecutive bases in the target region in the group consisting of positions 1905 to 1924, 1908 to 1927, 1914 to 1933, 1931 to 1950, 2117 to 2136, 2749 to 2768, 3100 to 3119 and 4125 to 4144.

作为与包含上述靶序列中的至少15个连续的碱基的核酸互补的反义寡核苷酸的例子，可列举包含下述碱基序列的反义寡核苷酸或由下述碱基序列构成的反义寡核苷酸：Examples of antisense oligonucleotides complementary to a nucleic acid comprising at least 15 consecutive bases in the target sequence include antisense oligonucleotides comprising or consisting of the following base sequences:

(i)选自由序列号7、10、12、13、25、27、28、30、61～65、68～72、76～78、83～85、90、91、112～114、137、146和159组成的组中的碱基序列；(i) a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61-65, 68-72, 76-78, 83-85, 90, 91, 112-114, 137, 146 and 159;

(ii)在选自由序列号7、10、12、13、25、27、28、30、61～65、68～72、76～78、83～85、90、91、112～114、137、146和159组成的组中的碱基序列中添加、缺失或置换1个或数个碱基而成的碱基序列；或(ii) a base sequence in which one or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146 and 159; or

(iii)相对于选自由序列号7、10、12、13、25、27、28、30、61～65、68～72、76～78、83～85、90、91、112～114、137、146和159组成的组中的碱基序列具有90％以上的序列一致性的碱基序列，(iii) a nucleotide sequence having a sequence identity of 90% or more to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146 and 159,

例如，(i)的碱基序列。For example, the base sequence of (i).

一个实施方式中，本发明的反义寡核苷酸抑制靶区域的功能。本说明书中，“抑制靶区域的功能”包括下述中的一种以上：与靶区域结合并通过RNaseH将包含与反义寡核苷酸形成了双链的靶区域的基因组RNA切割、抑制包含靶区域的基因组RNA的复制、在翻译靶区域时抑制其翻译、及抑制包含靶区域的基因组RNA的转录。本说明书中，“亚基因组RNA”是指如下RNA：将以(+)链的基因组RNA为模板由RNA依赖性RNA聚合酶合成的(-)链的RNA的一部分作为模板由RNA依赖性RNA聚合酶合成，比基因组RNA短，作为用于病毒蛋白合成(翻译)的mRNA起作用的RNA。In one embodiment, the antisense oligonucleotide of the present invention inhibits the function of the target region. In this specification, "inhibiting the function of the target region" includes one or more of the following: binding to the target region and cutting the genomic RNA of the target region that forms a double strand with the antisense oligonucleotide by RNaseH, inhibiting the replication of the genomic RNA containing the target region, inhibiting its translation when translating the target region, and inhibiting the transcription of the genomic RNA containing the target region. In this specification, "subgenomic RNA" refers to the following RNA: a part of the RNA of the (-) chain synthesized by RNA-dependent RNA polymerase using the genomic RNA of the (+) chain as a template is synthesized by RNA-dependent RNA polymerase, which is shorter than the genomic RNA and acts as an mRNA for viral protein synthesis (translation).

本发明的反义寡核苷酸可以使用各种自动合成装置(例如AKTA oligopilot plus10/100(GE Healthcare))容易地合成，或者，也可以委托第三方机构(例如，Promega公司或Takara公司)等进行制作。The antisense oligonucleotide of the present invention can be easily synthesized using various automatic synthesizers (eg, AKTA oligopilot plus 10/100 (GE Healthcare)), or can be produced by outsourcing to a third party organization (eg, Promega Corporation or Takara Corporation).

一个实施方式中，本发明涉及一种药物组合物，其包含反义寡核苷酸或其药学上可接受的盐或它们的水合物。在向对象给药本发明的反义寡核苷酸时，本发明的药物组合物可以包含促进反义寡核苷酸的递送的载体。这样的载体只要药学上可以接受就没有特别限制，作为其例子，可以列举出阳离子性脂质体、阳离子性聚合物等阳离子性载体、或利用了病毒包膜的载体。作为阳离子性脂质体，例如可以列举出将2-O-(2-二乙基氨基乙基)氨基甲酰基-1,3-O-二油酰甘油和磷脂作为必须构成成分所形成的脂质体(以下称为“脂质体A”)、Oligofectamine(注册商标)(Invitrogen公司制)、Lipofectin(注册商标)(Invitrogen公司制)、Lipofectamine(注册商标)(Invitrogen公司制)、Lipofectamine2000(注册商标)(Invitrogen公司制)、DMRIE-C(注册商标)(Invitrogen公司制)、GeneSilencer(注册商标)(Gene Therapy Systems公司制)、TransMessenger(注册商标)(QIAGEN公司制)、TransIT TKO(注册商标)(Mirus公司制)、Nucleofector II(Lonza)。作为阳离子性聚合物，例如可以列举出JetSI(注册商标)(Qbiogene公司制)、Jet-PEI(注册商标)(聚乙烯亚胺、Qbiogene公司制)。作为利用了病毒包膜的载体，例如可以列举出GenomeOne(注册商标)(HVJ-E脂质体、石原产业公司制)。或者，可以使用日本专利2924179号中记载的医药设备、日本再公表专利公报第2006/129594号和日本再公表专利公报第2008/096690号中记载的阳离子性载体。In one embodiment, the present invention relates to a pharmaceutical composition comprising an antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof. When the antisense oligonucleotide of the present invention is administered to a subject, the pharmaceutical composition of the present invention may include a carrier that promotes the delivery of the antisense oligonucleotide. Such a carrier is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include cationic carriers such as cationic liposomes, cationic polymers, or carriers utilizing viral envelopes. Examples of cationic liposomes include liposomes formed by using 2-O-(2-diethylaminoethyl)carbamoyl-1,3-O-dioleoylglycerol and phospholipids as essential components (hereinafter referred to as "liposome A"), Oligofectamine (registered trademark) (manufactured by Invitrogen), Lipofectin (registered trademark) (manufactured by Invitrogen), Lipofectamine (registered trademark) (manufactured by Invitrogen), Lipofectamine 2000 (registered trademark) (manufactured by Invitrogen), DMRIE-C (registered trademark) (manufactured by Invitrogen), GeneSilencer (registered trademark) (manufactured by Gene Therapy Systems), TransMessenger (registered trademark) (manufactured by QIAGEN), TransIT TKO (registered trademark) (manufactured by Mirus), and Nucleofector II (Lonza). Examples of cationic polymers include JetSI (registered trademark) (manufactured by Qbiogene) and Jet-PEI (registered trademark) (polyethyleneimine, manufactured by Qbiogene). As a carrier utilizing a viral envelope, for example, GenomeOne (registered trademark) (HVJ-E liposome, manufactured by Ishihara Sangyo Co., Ltd.) can be cited. Alternatively, a medical device described in Japanese Patent No. 2924179, a cationic carrier described in Japanese Re-Publication Patent Gazette No. 2006/129594 and Japanese Re-Publication Patent Gazette No. 2008/096690 can be used.

一个实施方式中，为了促进反义寡核苷酸的递送，本发明的反义寡核苷酸在药物组合物中也可以成为与脂质等的复合体(缀合物)。例如可以如Bijsterbosch,M.K.et al.(2000)Nucleic Acid Res.,28,2717-2725中所记载那样成为与胆固醇的缀合物。In one embodiment, in order to facilitate the delivery of the antisense oligonucleotide, the antisense oligonucleotide of the present invention may be a complex (conjugate) with a lipid or the like in a pharmaceutical composition. For example, it may be a conjugate with cholesterol as described in Bijsterbosch, M.K. et al. (2000) Nucleic Acid Res., 28, 2717-2725.

本发明的药物组合物除了包含反义寡核苷酸或其药学上可接受的盐或它们的水合物和任选的上述载体之外，也可以包含药学上可接受的添加剂。作为上述添加剂，例如可以列举出乳化辅助剂(例如，碳数6～22的脂肪酸、其药学上可接受的盐、白蛋白、葡聚糖)、稳定剂(例如，胆固醇、磷脂酸、甘露糖醇、山梨糖醇)、等渗剂(例如，氯化钠、葡萄糖、麦芽糖、乳糖、蔗糖、海藻糖)、pH调节剂(例如，盐酸、硫酸、磷酸、乙酸、氢氧化钠、氢氧化钾、三乙醇胺)。可以使用这些中的一种或两种以上。本发明的组合物中的该添加剂的含量为90重量％以下是适合的，优选70重量％以下，更优选50重量％以下。In addition to the antisense oligonucleotide or its pharmaceutically acceptable salt or its hydrate and the optional above-mentioned carrier, the pharmaceutical composition of the present invention may also contain a pharmaceutically acceptable additive. As the above-mentioned additive, for example, emulsification aids (for example, fatty acids with carbon numbers 6 to 22, pharmaceutically acceptable salts thereof, albumin, dextran), stabilizers (for example, cholesterol, phosphatidic acid, mannitol, sorbitol), isotonic agents (for example, sodium chloride, glucose, maltose, lactose, sucrose, trehalose), pH regulators (for example, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, triethanolamine) can be listed. One or more of these can be used. It is suitable that the content of the additive in the composition of the present invention is 90% by weight or less, preferably 70% by weight or less, and more preferably 50% by weight or less.

本发明的药物组合物的制备法没有限定，例如可以通过在载体的分散液中加入本发明的反义寡核苷酸并进行适当搅拌来制备。另外，添加剂可以在本发明的反义寡核苷酸添加前或添加后的适合的工序中添加。作为添加本发明的反义寡核苷酸时可以使用的水性介质，只要是药学上可接受的物质就没有特别限制，例如可以列举出注射用水、注射用蒸馏水、生理盐水等电解质液、葡萄糖液、麦芽糖液等糖液。另外，关于上述情况的pH和温度等的条件，本领域技术人员可以进行适宜选择。The preparation method of the pharmaceutical composition of the present invention is not limited, for example, it can be prepared by adding the antisense oligonucleotide of the present invention to the dispersion of the carrier and stirring appropriately. In addition, the additive can be added in a suitable process before or after the antisense oligonucleotide of the present invention is added. As an aqueous medium that can be used when adding the antisense oligonucleotide of the present invention, as long as it is a pharmaceutically acceptable substance, there is no particular limitation, for example, electrolyte solutions such as water for injection, distilled water for injection, physiological saline, glucose solution, maltose solution, etc. can be listed. In addition, about the conditions of pH and temperature of the above situation, those skilled in the art can make appropriate selections.

本发明的药物组合物例如可以制成液剂、其冷冻干燥制剂。该冷冻干燥制剂可以通过利用常规方法对具有液剂型态的本发明的组合物进行冷冻干燥处理而制备。例如，可以对具有液剂型态的本发明的组合物进行适合的灭菌后，将规定量分注在小瓶中，在约-40℃～-20℃的范围内的条件下进行2小时左右预冷冻，在约0℃～10℃的范围内在减压下进行一次干燥，接着，在约15℃～25℃的范围内在减压下进行二次干燥来进行冷冻干燥。此外，通常用氮气置换小瓶内部，密封，能够得到本发明的组合物的冷冻干燥制剂。The pharmaceutical composition of the present invention can be prepared into a liquid or a freeze-dried preparation thereof, for example. The freeze-dried preparation can be prepared by freeze-drying the composition of the present invention in a liquid dosage form using a conventional method. For example, the composition of the present invention in a liquid dosage form can be sterilized appropriately, and then a prescribed amount can be dispensed into a vial, pre-frozen for about 2 hours under conditions in the range of about -40°C to -20°C, dried once under reduced pressure in the range of about 0°C to 10°C, and then freeze-dried by performing a secondary drying under reduced pressure in the range of about 15°C to 25°C. In addition, the inside of the vial is usually replaced with nitrogen and sealed to obtain a freeze-dried preparation of the composition of the present invention.

本发明的药物组合物的冷冻干燥制剂通常可以通过添加任意适合的溶液(再溶解液)进行再溶解来使用。作为这样的再溶解液，可以列举出注射用水、生理盐水、其他普通输液。该再溶解液的液量根据用途等而不同，没有特别限制，冷冻干燥前的液量的0.5倍量～2倍量或500mL以下是适合的。The freeze-dried preparation of the pharmaceutical composition of the present invention can be used by adding any suitable solution (redissolved liquid) to redissolve. As such a redissolved liquid, water for injection, physiological saline, other common infusions can be listed. The liquid volume of the redissolved liquid is different according to the purpose, and is not particularly limited. 0.5 times to 2 times or less than 500mL of the liquid volume before freeze drying is suitable.

作为给药本发明的药物组合物时的用量，理想的是考虑所含的本发明的反义寡核苷酸的种类、剂形、年龄和体重等患者状态、给药途径、疾病性质和程度而进行调节，对于成人，以本发明的反义寡核苷酸的量计，1次给药中，可以每千克体重给药0.01mg～20mg、优选每千克体重给药0.03mg～10mg、进一步优选每千克体重给药0.05mg～4mg、更优选每千克体重给药0.1mg～2mg。给药频率可以为1～3天1次、1周1次或2～3周1次。也存在该数值根据目标疾病的种类、给药方式、靶分子而不同的情况。因此，根据情况，该数值以下的用量或给药频率有时也是充分的，另外，相反地，有时也需要该数值以上的用量或给药频率。As the dosage for administering the pharmaceutical composition of the present invention, it is ideal to consider the type of antisense oligonucleotide of the present invention, dosage form, age and weight of the patient, route of administration, nature and degree of the disease and adjust it. For adults, based on the amount of the antisense oligonucleotide of the present invention, 0.01 mg to 20 mg per kilogram of body weight can be administered in one administration, preferably 0.03 mg to 10 mg per kilogram of body weight, further preferably 0.05 mg to 4 mg per kilogram of body weight, and more preferably 0.1 mg to 2 mg per kilogram of body weight. The frequency of administration can be once every 1 to 3 days, once a week, or once every 2 to 3 weeks. There are also cases where this value is different depending on the type of target disease, mode of administration, and target molecule. Therefore, depending on the situation, the dosage or administration frequency below this value is sometimes sufficient. In addition, on the contrary, the dosage or administration frequency above this value is sometimes required.

本发明的药物组合物的给药方式只要为药物上可接受的给药方式则没有特别限制，可以根据治疗方法来选择，可列举例如静脉内给药、动脉内给药、肌肉内给药、皮下给药、经口给药、组织内给药、经皮给药、经肺给药、经鼻给药、向中枢神经给药等。作为向中枢神经给药的例子，可列举髓腔内给药、颅内给药、例如脑室内给药或侧脑室给药、脑实质内给药和软脑膜(软脑脊膜)下给药。另外，作为本发明的组合物可采取的剂型，没有特别限制，可列举例如各种注射剂、经口剂、点滴剂、吸入剂、软膏剂、洗剂、巴布剂等。The administration method of the pharmaceutical composition of the present invention is not particularly limited as long as it is a pharmaceutically acceptable administration method, and can be selected according to the treatment method, and examples thereof include intravenous administration, intraarterial administration, intramuscular administration, subcutaneous administration, oral administration, intratissue administration, transdermal administration, pulmonary administration, nasal administration, administration to the central nervous system, etc. As examples of administration to the central nervous system, intramedullary administration, intracranial administration, such as intraventricular administration or lateral ventricle administration, intraparenchymal administration, and administration under the pia mater (piater). In addition, the dosage form that can be taken as the composition of the present invention is not particularly limited, and examples thereof include various injections, oral agents, drops, inhalants, ointments, lotions, and cataplasms.

本发明的反义寡核苷酸或药物组合物的给药对象可列举例如：哺乳动物、例如人等灵长类；大鼠、小鼠和褐家鼠等实验动物；猪、牛、马和绵羊等家畜动物等，优选人。The subjects to whom the antisense oligonucleotide or pharmaceutical composition of the present invention is administered include, for example, mammals, such as primates such as humans; experimental animals such as rats, mice and rats; domestic animals such as pigs, cattle, horses and sheep, etc., preferably humans.

一个实施方式中，本发明涉及齿状核红核苍白球路易体萎缩症(DRPLA)的治疗和/或预防方法，其包括将本发明的反义寡核苷酸或其药物上可接受的盐或者它们的水合物、或者药物组合物给药于对象的工序。本实施方式中的药物组合物、以及药物组合物的给药量和给药途径等如本说明书的记载。In one embodiment, the present invention relates to a method for treating and/or preventing dentatorubral pallidum Lewy body atrophy (DRPLA), comprising administering an antisense oligonucleotide of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof, or a pharmaceutical composition to a subject. The pharmaceutical composition in this embodiment, and the dosage and route of administration of the pharmaceutical composition are as described in this specification.

本说明书中，齿状核红核苍白球路易体萎缩症(DRPLA)的治疗包括缓和、改善和缓解齿状核红核苍白球路易体萎缩症或其症状(例如儿童情况下的共济失调、肌阵挛、癫痫和进行性智力退化、成人情况下的共济失调、舞蹈徐动症(choreoathetosis)、痴呆症或性格变化中的一种以上)。本说明书中，预防DRPLA包括降低发生DRPLA或其症状的风险。In this specification, the treatment of dentatorubral nucleus pallidum Lewy body atrophy (DRPLA) includes relieving, improving and alleviating dentatorubral nucleus pallidum Lewy body atrophy or its symptoms (e.g., ataxia, myoclonus, epilepsy and progressive mental degeneration in children, ataxia, choreoathetosis, dementia or personality changes in adults). In this specification, preventing DRPLA includes reducing the risk of DRPLA or its symptoms.

【实施例】[Example]

以下列举实施例和试验例进一步详细地说明本发明，但是本发明不限于实施例所示的范围。The present invention will be described in further detail below with reference to Examples and Test Examples, but the present invention is not limited to the scope shown in the Examples.

“间隔寡核苷酸(gapmer)”被定义为：具有被2个相邻的非脱氧寡核苷酸片段夹着的2’-脱氧寡核苷酸的中间区域的低聚物化合物，通常为寡核苷酸。中间区域被称为“间隔(gap)”，相邻的片段被称为“侧翼(wing)”。本实施例中使用的间隔寡核苷酸具有被2个相邻的5个核苷酸的侧翼夹着的10个核苷酸的间隔。其被称为5-10-5间隔寡核苷酸。"Gapmer" is defined as an oligomeric compound, usually an oligonucleotide, having a middle region of a 2'-deoxyoligonucleotide sandwiched between two adjacent non-deoxyoligonucleotide fragments. The middle region is called the "gap" and the adjacent fragments are called "wings". The gapmer used in this example has a gap of 10 nucleotides sandwiched between two adjacent wings of 5 nucleotides. It is called a 5-10-5 gapmer oligonucleotide.

＜实施例1：间隔寡核苷酸(寡核苷酸)的合成＞<Example 1: Synthesis of spacer oligonucleotide (oligonucleotide)>

本实施例中使用的间隔寡核苷酸(寡核苷酸)通常可以按照W.Brad Wan等、Nucleic Acid Research，Vol.42,No.22 13456(2014)等中记载的方法来制造。The spacer oligonucleotide (oligonucleotide) used in this example can generally be produced according to the method described in W. Brad Wan et al., Nucleic Acid Research, Vol. 42, No. 22 13456 (2014) and the like.

本实施例中使用的间隔寡核苷酸中，侧翼的核苷具有式(a)所示的2’-甲氧基(2’-OMe)的具体寡核苷酸的一部分如上所述参照W.Brad Wan等、Nucleic Acid Research，Vol.42,No.22 13456(2014)中记载的方法来合成。另外，其余的委托株式会社ジーンデザイン进行合成而获得。Among the spacer oligonucleotides used in this example, a portion of the specific oligonucleotides having a 2'-methoxy group (2'-OMe) represented by the formula (a) as the flanking nucleoside was synthesized as described above with reference to the method described in W. Brad Wan et al., Nucleic Acid Research, Vol. 42, No. 22 13456 (2014). In addition, the rest was obtained by commissioning Zindezin Co., Ltd. to synthesize.

(式中，碱基为胞嘧啶(C)、尿嘧啶(U)、腺嘌呤(A)或鸟嘌呤(G)，Me为甲基。)(In the formula, the base is cytosine (C), uracil (U), adenine (A) or guanine (G), and Me is methyl.)

本实施例中使用的间隔寡核苷酸中，侧翼的核苷具有式(b)所示的2’-甲氧基乙基(2’-O-MOE)的具体寡核苷酸如上所述参照W.Brad Wan等、Nucleic Acid Research，Vol.42,No.22 13456(2014)中记载的方法来合成。Among the spacer oligonucleotides used in this example, the specific oligonucleotide in which the flanking nucleoside has a 2'-methoxyethyl group (2'-O-MOE) represented by formula (b) was synthesized as described above with reference to the method described in W. Brad Wan et al., Nucleic Acid Research, Vol. 42, No. 22 13456 (2014).

(式中，碱基为5-甲基胞嘧啶(C)、胸腺嘧啶(T)、腺嘌呤(A)或鸟嘌呤(G)，Me为甲基。)(In the formula, the base is 5-methylcytosine (C), thymine (T), adenine (A) or guanine (G), and Me is a methyl group.)

侧翼的核苷具有式(a)所示的2’-OMe基或式(b)所示的2’-O-MOE基的20mer的受试对象的间隔寡核苷酸(寡核苷酸)使用核酸自动合成机NTS M-8-MX DNA/RNA(日本テクノサービス株式会社)以1μmol规模来合成。链长的延伸使用标准亚磷酰胺方案(固相载体：GlenUnySupport，硫化使用DDTT([(N,N-二甲基氨基亚甲基)氨基]-3H-1,2,4-二噻唑-3-硫酮)等，氧化使用0.02M的碘/四氢呋喃：吡啶：水＝7：1：2等)来实施，得到末端的5’位的羟基用二甲氧基三苯甲基(DMTr)保护且3’位负载于固相的寡核苷酸。接着，用从富士胶片和光株式会社获得的脱封闭溶液-1进行处理而去除DMTr基后，进行氨处理，由此将目标物从固相载体切出。馏去溶剂，将得到的粗产物用反相HPLC进行纯化，由此得到目标物。A 20-mer test subject spacer oligonucleotide (oligonucleotide) having a 2'-OMe group represented by formula (a) or a 2'-O-MOE group represented by formula (b) as a flanking nucleoside was synthesized on a 1 μmol scale using a nucleic acid automatic synthesizer NTS M-8-MX DNA/RNA (Japan Technosapiens Co., Ltd.). Chain extension was performed using a standard phosphoramidite protocol (solid phase support: GlenUnySupport, sulfurization using DDTT ([(N,N-dimethylaminomethylene)amino]-3H-1,2,4-dithiazole-3-thione) etc., oxidation using 0.02M iodine/tetrahydrofuran:pyridine:water=7:1:2 etc.), and the hydroxyl group at the terminal 5' position was protected with a dimethoxytrityl group (DMTr) and the 3' position was supported on a solid phase. Next, the DMTr group was removed by treating with a deblocking solution-1 obtained from Fujifilm Wako Co., Ltd., and then the target product was excised from the solid support by treating with ammonia. The solvent was distilled off, and the obtained crude product was purified by reverse phase HPLC to obtain the target product.

＜实施例2：受试对象的间隔寡核苷酸(寡核苷酸)的设计＞<Example 2: Design of spacer oligonucleotide (oligonucleotide) of the subject>

以靶向人atrophin-1(ATN1)(Gen Bank：NM＿001007026、序列号471)的反义寡核苷酸(ASO)的方式设计受试对象的间隔寡核苷酸(寡核苷酸)。将用DNA的碱基表示的寡核苷酸序列示于表1、表2、表3、表4。The test subject spacer oligonucleotide (oligonucleotide) was designed as an antisense oligonucleotide (ASO) targeting human atrophin-1 (ATN1) (Gen Bank: NM_001007026, SEQ ID NO: 471). The oligonucleotide sequences expressed as DNA bases are shown in Tables 1, 2, 3, and 4.

表1和表2中，寡核苷酸全部为5-10-5的间隔寡核苷酸，核苷之间的键全部为硫代磷酸酯(P＝S)。另外，关于表1的具有2’-OMe基的间隔寡核苷酸，侧翼部分的T(胸腺嘧啶)实际为U(尿嘧啶)。另外，关于表2的具有2’-O-MOE基的间隔寡核苷酸，间隔部分和侧翼部分的C(胞嘧啶)实际为甲基C，侧翼部分的T实际为T。In Tables 1 and 2, all oligonucleotides are 5-10-5 spacer oligonucleotides, and all bonds between nucleosides are phosphorothioate (P=S). In addition, regarding the spacer oligonucleotides having a 2'-OMe group in Table 1, the T (thymine) in the flanking part is actually U (uracil). In addition, regarding the spacer oligonucleotides having a 2'-O-MOE group in Table 2, the C (cytosine) in the spacer part and the flanking part is actually methyl C, and the T in the flanking part is actually T.

【表1】【Table 1】

表1在侧翼的核苷中具有2′-OMe基的受试对象的间隔寡核苷酸(寡核苷酸)Table 1. Subject spacer oligonucleotides (oligonucleotides) with 2′-OMe groups in the flanking nucleosides

【表2-1】【table 2-1】

表2在侧翼的核苷中具有2′-O-MOE基的受试对象的间隔寡核苷酸(寡核苷酸)Table 2: Interval oligonucleotides (oligonucleotides) of subjects having 2′-O-MOE groups in the flanking nucleosides

【表2-2】【Table 2-2】

【表2-3】【Table 2-3】

【表2-4】【Table 2-4】

【表2-5】【Table 2-5】

【表2-6】【Table 2-6】

【表2-7】【Table 2-7】

表3中，寡核苷酸全部为具有2’-O-MOE基的5-10-5的间隔寡核苷酸，5’侧翼部分和3’侧翼部分的核苷之间的键为硫代磷酸酯(P＝S)或磷酸二酯(P＝O)，间隔部分的核苷之间的键全部为硫代磷酸酯(P＝S)。表3中，用＾表示作为磷酸二酯(P＝O)的键。另外，间隔部分和侧翼部分的C实际为甲基C，侧翼部分的T实际为T。In Table 3, all oligonucleotides are 5-10-5 spacer oligonucleotides having a 2'-O-MOE group, the bonds between the nucleosides in the 5' wing part and the 3' wing part are phosphorothioate (P=S) or phosphodiester (P=O), and the bonds between the nucleosides in the spacer part are all phosphorothioate (P=S). In Table 3, the bonds that are phosphodiester (P=O) are represented by ＾. In addition, C in the spacer part and the wing part is actually methyl C, and T in the wing part is actually T.

【表3】【table 3】

表3侧翼的核苷之间的键包含磷酸二酯键的受试对象的间隔寡核苷酸(寡核苷酸)Table 3 Spacer oligonucleotides (oligonucleotides) of subjects in which the bonds between the flanking nucleosides contain phosphodiester bonds

^：磷酸二酯键^: phosphodiester bond

表4中，寡核苷酸全部为具有2’-O-MOE基的5-10-5的间隔寡核苷酸，5’侧翼部分和3’侧翼部分的核苷之间的键为硫代磷酸酯(P＝S)或磷酸二酯(P＝O)，间隔部分的核苷之间的键全部为硫代磷酸酯(P＝S)。表4中，用＾表示作为磷酸二酯(P＝O)的键。另外，间隔部分和侧翼部分的C实际为甲基C，侧翼部分的T实际为T，3’侧翼部分的带有下划线的碱基为与序列号196不同的碱基。In Table 4, all oligonucleotides are 5-10-5 spacer oligonucleotides having a 2'-O-MOE group, the bonds between the nucleosides in the 5' wing part and the 3' wing part are phosphorothioate (P=S) or phosphodiester (P=O), and the bonds between the nucleosides in the spacer part are all phosphorothioate (P=S). In Table 4, ＾ represents the bonds that are phosphodiester (P=O). In addition, C in the spacer part and the wing part is actually methyl C, T in the wing part is actually T, and the underlined base in the 3' wing part is a base different from that in SEQ ID NO: 196.

【表4】【Table 4】

表4 3′侧翼中与序列号196有一个碱基不同的受试对象的间隔寡核苷酸(寡核苷酸)Table 4 Interval oligonucleotides (oligonucleotides) of the subject having one base difference in the 3′ flank from SEQ ID NO: 196

^：磷酸二酯键^: phosphodiester bond

下划线：与序列号196不同的碱基Underline: bases different from sequence number 196

[试验例1]使用A204人横纹肌肉瘤细胞株测定间隔寡核苷酸的ATN-1基因敲除活性(抑制活性)[Test Example 1]Determination of ATN-1 gene knockoutactivity (inhibitory activity) of spacer oligonucleotides using A204 human rhabdomyosarcoma cell line

对于3.0×10⁵个A204细胞(由ATCC获得)，按照SF Cell Line 4D-Nucleofector(TM)X KitS试剂盒附带的方案通过4D-Nucleofector(TM)以1μM或2μM的浓度导入表1或表2的受试对象的间隔寡核苷酸或阳性对照的间隔寡核苷酸。程序使用DS-130。导入后，将细胞在包含10％胎牛血清(FBS)(NICHIREI)和1mM L-谷氨酰胺(Gibco)的McCoy’s 5A培养基(SIGMA)中在37℃、5％CO₂条件下培养一晚。作为阳性对照的间隔寡核苷酸，使用进行预备试验(数据未示出)而确认了活性的侧翼的核苷具有2’-OMe基的OMe-6(5’-AGAGACCTGGTCCAAGATTC-3’、序列号472)或侧翼的核苷具有2’-O-MOE基的NRH-71(5’-AGAGACCTGGTCCAAGATTC-3’、序列号472)。两寡核苷酸均为5-10-5的间隔寡核苷酸，核苷之间的键全部为硫代磷酸酯(P＝S)。另外，关于OMe-6，侧翼部分的T(胸腺嘧啶)实际为U(尿嘧啶)。另外，关于NRH-71，间隔部分和侧翼部分的C(胞嘧啶)实际为甲基C，侧翼部分的T实际为T。这些阳性对照的间隔寡核苷酸也与受试对象的间隔寡核苷酸同样地进行合成。次日，将细胞用PBS(NACALAI TESQUE)清洗后，添加包含1％的2-巯基乙醇(NACALAI TESQUE)的RA1(宝生物)将细胞溶解，回收至NucleoSpin(R)Filter(宝生物)上。通过离心去除不溶级分后，按照NucleoSpin(R)RNA(宝生物)所附带的方案提取总RNA。使用NanoDrop(ThermoFisher)测定提取而得的总RNA的浓度。相对于提取的总RNA 200ng，使用High CapacitycDNAReverse Transcription Kit(applied biosystems)和试剂盒所附带的随机引物进行逆转录(RT)反应。具体而言，按照上述试剂盒所附带的方案制备反应液。热循环仪使用TaKaRa PCR Thermal Cycler Dice Touch(宝生物)。使用的RT反应的程序如下。3.0×10⁵ A204 cells (obtained from ATCC) were introduced into the intervening oligonucleotides of the subjects or the intervening oligonucleotides of the positive control at a concentration of 1 μM or 2 μM by 4D-Nucleofector (TM) according to the protocol attached to the SF Cell Line 4D-Nucleofector (TM) X KitS kit. The procedure used DS-130. After the introduction, the cells were cultured overnight at 37°C and 5% CO₂ in McCoy's 5A medium (SIGMA) containing 10% fetal bovine serum (FBS) (NICHIREI) and 1 mM L-glutamine (Gibco). As positive control spacer oligonucleotides, OMe-6 (5'-AGAGACCTGGTCCAAGATTC-3', sequence number 472) in which the flanking nucleoside has a 2'-OMe group, or NRH-71 (5'-AGAGACCTGGTCCAAGATTC-3', sequence number 472) in which the flanking nucleoside has a 2'-O-MOE group, which was confirmed to be active in preliminary experiments (data not shown) was used. Both oligonucleotides are 5-10-5 spacer oligonucleotides, and all the bonds between nucleosides are phosphorothioates (P=S). In addition, for OMe-6, the T (thymine) in the flanking part is actually U (uracil). In addition, for NRH-71, the C (cytosine) in the spacer part and the flanking part is actually methyl C, and the T in the flanking part is actually T. These positive control spacer oligonucleotides were also synthesized in the same way as the spacer oligonucleotides of the test subject. The next day, the cells were washed with PBS (NACALAI TESQUE), and RA1 (Takara Biotech) containing 1% 2-mercaptoethanol (NACALAI TESQUE) was added to dissolve the cells and recovered on NucleoSpin (R) Filter (Takara Biotech). After removing the insoluble fraction by centrifugation, total RNA was extracted according to the protocol attached to NucleoSpin (R) RNA (Takara Biotech). The concentration of the extracted total RNA was measured using NanoDrop (ThermoFisher). Reverse transcription (RT) reaction was performed using High Capacity cDNA Reverse Transcription Kit (applied biosystems) and random primers attached to the kit with respect to 200 ng of extracted total RNA. Specifically, the reaction solution was prepared according to the protocol attached to the above-mentioned kit. The thermal cycler used was TaKaRa PCR Thermal Cycler Dice Touch (Takara Biotech). The procedure for the RT reaction used is as follows.

25℃、10分钟：引物的退火25°C, 10 minutes: Primer annealing

37℃、120分钟：逆转录反应37°C, 120 minutes: Reverse transcription reaction

85℃、5分钟：逆转录酶失活85℃, 5 minutes: reverse transcriptase inactivation

之后，使用Fast SYBR Green Master Mix(Thermo Fisher Scientific)以RT反应液为模板进行qPCR，测定A204细胞内源表达的ATN1的RNA表达量。qPCR反应中，使用ATN1内的2个序列(外显子4～外显子5、外显子6～外显子7)作为模板。具体而言，按照上述试剂盒所附带的方案制备反应液。qPCR使用QuantStudio6Flex Real-Time PCR System(appliedbiosystems)。使用的qPCR的程序如下。Afterwards, qPCR was performed using Fast SYBR Green Master Mix (Thermo Fisher Scientific) with the RT reaction solution as a template to measure the RNA expression level of ATN1 endogenously expressed in A204 cells. In the qPCR reaction, two sequences in ATN1 (exon 4 to exon 5, exon 6 to exon 7) were used as templates. Specifically, the reaction solution was prepared according to the protocol attached to the above kit. qPCR used QuantStudio6Flex Real-Time PCR System (applied biosystems). The qPCR program used is as follows.

50℃、2分钟；95℃、10分钟：聚合酶活化、cDNA热变性50℃, 2 minutes; 95℃, 10 minutes: polymerase activation, cDNA thermal denaturation

[95℃、15秒；60℃、1分钟]×40循环：PCR扩增[95°C, 15 seconds; 60°C, 1 minute] × 40 cycles: PCR amplification

95℃、15秒；60℃、1分钟→95℃、15秒(Melting Curve 0.05℃/s)：熔解曲线分析95℃, 15 seconds; 60℃, 1 minute → 95℃, 15 seconds (Melting Curve 0.05℃/s): Melting curve analysis

将ATN1 RNA的检测中使用的引物示于表4。ATN1 RNA表达量用管家基因即β-肌动蛋白RNA表达量进行校正。将β-肌动蛋白RNA的检测中使用的引物示于表4。由导入受试物质即间隔寡核苷酸时的ATN1 RNA表达量的比率计算相对于不添加间隔寡核苷酸而仅进行基于4D-Nucleofector(TM)的导入操作的细胞的ATN1 RNA表达量的抑制比例，分析受试物质即间隔寡核苷酸的抑制活性。将结果示于表5～9。The primers used in the detection of ATN1 RNA are shown in Table 4. The expression level of ATN1 RNA was corrected by the expression level of β-actin RNA, a housekeeping gene. The primers used in the detection of β-actin RNA are shown in Table 4. The inhibition ratio of the expression level of ATN1 RNA when the test substance, i.e., the spacer oligonucleotide, was calculated relative to the inhibition ratio of the expression level of ATN1 RNA in cells that were only introduced by the 4D-Nucleofector (TM) without adding the spacer oligonucleotide, and the inhibitory activity of the test substance, i.e., the spacer oligonucleotide, was analyzed. The results are shown in Tables 5 to 9.

【表5-1】【Table 5-1】

表5-1用于检测内源性ATN1RNA的引物和识别的外显子位点Table 5-1 Primers used to detect endogenous ATN1 RNA and the exon sites identified

【表5-2】【Table 5-2】

表5-2用于检测作为校正用基因的β-肌动蛋白RNA的引物Table 5-2 Primers for detecting β-actin RNA as a correction gene

【表6-1】【Table 6-1】

表6给药了在侧翼的核苷中具有2′-OMe基的间隔寡核苷酸(2.0μM)的A204细胞中的ATN-1基因表达量比Table 6 Comparison of ATN-1 gene expression levels in A204 cells administered with spacer oligonucleotides having 2′-OMe groups in flanking nucleosides (2.0 μM)

【表6-2】【Table 6-2】

29290.390.391.101.100.470.471.271.271.191.19292930300.110.110.320.320.130.130.340.340.330.33303031310.430.430.940.940.490.491.021.020.980.98313132320.790.792.282.280.760.762.052.052.162.16323233330.690.691.511.510.710.711.491.491.501.50333334340.790.791.721.720.920.921.931.931.821.82343435350.790.791.721.720.890.891.871.871.801.80353536360.840.841.821.820.800.801.681.681.751.75363637370.740.741.621.620.770.771.621.621.621.62373739390.750.751.631.630.840.841.761.761.691.69393940400.820.822.352.350.800.802.152.152.252.25404041410.640.641.391.390.550.551.151.151.271.27414142420.580.581.661.660.530.531.431.431.541.54424243430.800.801.751.750.900.901.901.901.821.82434344440.610.611.331.330.630.631.471.471.401.40444445450.380.381.091.090.360.360.960.961.031.03454546460.920.922.002.000.920.922.142.142.072.07464647470.860.861.871.870.860.862.002.001.941.94474748480.380.381.091.090.440.441.181.181.131.13484849490.560.561.211.210.530.531.231.231.221.22494950500.720.721.561.560.690.691.601.601.581.58505052520.440.441.031.030.470.471.081.081.061.06525253530.800.802.032.030.830.831.901.901.971.97535354540.750.751.631.630.780.781.811.811.721.72545455550.770.771.671.670.760.761.781.781.721.72555556560.620.621.341.340.630.631.461.461.401.40565657570.980.982.142.141.001.002.472.472.302.30575758580.680.681.261.260.700.701.211.211.231.235858

【表7】【Table 7】

表7给药了在侧翼的核苷中具有2′-OMe基的间隔寡核苷酸(1.0μM)的A204细胞中的ATN-1基因表达量比Table 7 Comparison of ATN-1 gene expression levels in A204 cells administered with spacer oligonucleotides having 2′-OMe groups in flanking nucleosides (1.0 μM)

【表8-1】【Table 8-1】

给药了在侧翼的核苷中具有2′-O-MOE基的间隔寡核苷酸(2.0μM)的A204细胞中的ATN-1基因表达量比Comparison of ATN-1 gene expression in A204 cells administered with a spacer oligonucleotide having a 2′-O-MOE group in the flanking nucleoside (2.0 μM)

【表8-2】【Table 8-2】

1301300.530.531.281.280.560.561.331.331.311.311231231311310.890.892.142.140.760.761.811.811.981.981241241321320.420.421.001.000.480.481.131.131.071.071251251331330.230.230.560.560.240.240.570.570.560.561261261341340.430.431.041.040.430.431.021.021.031.031271271391390.130.130.310.310.100.100.240.240.270.271321321441440.230.230.560.560.060.060.140.140.350.351371371451450.650.651.551.550.560.561.341.341.441.441381381501500.140.140.350.350.050.050.120.120.240.241431431521520.230.230.560.560.230.230.530.530.550.551451451531530.170.170.410.410.230.230.540.540.480.481461461541540.510.511.351.350.510.511.351.351.351.351471471551550.240.240.650.650.220.220.590.590.620.621481481561560.360.360.960.960.410.411.091.091.031.031491491571570.580.581.551.550.510.511.351.351.451.451501501581580.220.220.590.590.200.200.520.520.560.561511511591590.320.320.860.860.270.270.720.720.790.791521521601600.230.230.610.610.210.210.540.540.580.581531531611610.200.200.530.530.200.200.530.530.530.531541541621620.450.451.191.190.440.441.171.171.181.181551551631630.380.381.001.000.330.330.870.870.930.931561561641640.240.240.630.630.210.210.550.550.590.591571571651650.580.581.531.530.590.591.571.571.551.551581581661660.120.120.310.310.110.110.280.280.290.291591591681680.150.150.390.390.140.140.370.370.380.38161161

【表9】【Table 9】

给药了在侧翼的核苷中具有2′-O-MOE基的间隔寡核苷酸(1.0μM)的A204细胞中的ATN-1基因表达量比Comparison of ATN-1 gene expression in A204 cells administered with a spacer oligonucleotide having a 2′-O-MOE group in the flanking nucleoside (1.0 μM)

【表10-1】【Table 10-1】

给药了在侧翼的核苷中具有2′-O-MOE基的间隔寡核苷酸(0.5μM)的A204细胞中的ATN-1基因表达量比Comparison of ATN-1 gene expression in A204 cells administered with a spacer oligonucleotide having a 2′-O-MOE group in the flanking nucleoside (0.5 μM)

【表10-2】【Table 10-2】

1191190.350.350.430.430.370.370.420.420.430.431141141221220.670.670.800.800.660.660.900.900.850.851171171241240.310.310.370.370.290.290.390.390.380.3830301251250.970.971.171.170.800.801.091.091.131.131181181351350.560.560.690.690.510.510.580.580.640.641281281361360.790.790.980.980.740.740.830.830.910.911291291371370.470.470.580.580.470.470.530.530.560.561301301381380.380.380.460.460.380.380.430.430.450.451311311401400.250.250.300.300.220.220.250.250.280.281331331411410.450.450.560.560.470.470.540.540.550.551341341421420.920.921.141.140.860.860.970.971.051.051351351431430.650.650.840.840.670.670.790.790.820.821361361461460.960.961.161.160.950.951.091.091.121.121391391471470.640.640.770.770.720.720.830.830.800.801401401481480.850.851.021.020.850.850.980.981.001.001411411491490.900.901.131.130.910.911.121.121.131.131421421511510.800.800.970.970.820.820.950.950.960.961441441611610.500.500.720.720.590.590.730.730.730.731541541671670.250.250.320.320.250.250.300.300.310.311601601691690.490.490.630.630.510.510.600.600.610.611621621701700.390.390.500.500.420.420.500.500.500.50163163

【表11-1】【Table 11-1】

给药了在侧翼的核苷中具有2′-O-MOE基的间隔寡核苷酸(0.5μM)的A204细胞中的ATN-1基因表达量比Comparison of ATN-1 gene expression in A204 cells administered with a spacer oligonucleotide having a 2′-O-MOE group in the flanking nucleoside (0.5 μM)

【表11-2】【Table 11-2】

1971970.860.860.860.860.840.840.870.870.870.871891891981980.600.600.590.590.710.710.690.690.640.641901901991991.031.031.031.030.920.920.950.950.990.991911912002000.820.820.830.830.800.800.940.940.880.881921922012010.550.550.560.560.560.560.660.660.610.611931932022020.600.600.620.620.630.630.690.690.660.661941942032030.620.620.600.600.690.690.670.670.640.641951952042040.310.310.340.340.320.320.340.340.340.341961962052050.450.450.510.510.460.460.520.520.520.521971972062060.650.650.740.740.670.670.760.760.750.751981982072070.360.360.410.410.410.410.420.420.410.411991992082080.550.550.570.570.620.620.680.680.630.632002002092090.530.530.550.550.630.630.690.690.620.622012012102100.670.670.650.650.750.750.730.730.690.692022022112110.910.910.880.880.910.910.880.880.880.882032032122121.001.000.970.970.920.920.900.900.930.932042042132130.800.800.900.900.740.740.770.770.830.832052052142140.760.760.840.840.780.780.800.800.820.822062062152150.810.810.780.780.810.810.790.790.790.792072072162160.900.900.870.870.770.770.750.750.810.812082082172170.670.670.950.950.780.780.960.960.950.952092092182180.650.650.920.920.790.790.960.960.940.942102102192190.620.620.870.870.680.680.830.830.850.852112112202200.690.690.860.860.700.700.800.800.830.832122122212210.750.750.890.890.850.851.021.020.950.952132132222220.790.790.930.930.810.810.970.970.950.952142142232230.820.820.970.970.880.881.061.061.021.022152152242240.670.670.950.950.740.740.900.900.930.932162162252250.800.801.131.130.880.881.081.081.111.112172172262260.860.861.211.210.960.961.181.181.191.192182182272270.480.480.560.560.490.490.540.540.550.552192192282280.510.510.630.630.530.530.610.610.620.622202202292290.390.390.470.470.390.390.450.450.460.462212212302300.810.810.960.960.850.851.021.020.990.99222222

【表11-3】【Table 11-3】

2412410.690.690.670.670.690.690.670.670.670.672332332422420.800.800.770.770.900.900.870.870.820.822342343583580.720.720.810.810.720.720.740.740.780.783503503593590.730.730.710.710.670.670.650.650.680.683513513603600.750.750.720.720.710.710.690.690.710.713523523613610.730.730.710.710.690.690.670.670.690.693533533623620.820.820.800.800.800.800.780.780.790.793543543633630.880.880.850.850.900.900.880.880.860.863553554734730.450.450.580.580.450.450.580.580.580.584724724744740.480.480.620.620.410.410.540.540.580.584724724754750.550.550.710.710.440.440.580.580.640.644724724764760.430.430.560.560.470.470.610.610.590.594724724774770.640.640.830.830.610.610.800.800.820.824724724784780.580.580.740.740.510.510.660.660.700.704724724794790.570.570.740.740.480.480.620.620.680.684724724804800.090.090.110.110.100.100.130.130.120.121771774814810.100.100.130.130.140.140.180.180.160.161771774824820.130.130.170.170.130.130.170.170.170.171771774834830.070.070.090.090.070.070.090.090.090.091771774844840.190.190.250.250.170.170.230.230.240.241771774854850.160.160.200.200.130.130.160.160.180.181771774864860.100.100.130.130.080.080.100.100.120.121771774874870.440.440.440.440.410.410.420.420.430.431331334884880.260.260.260.260.280.280.290.290.280.281331334894890.390.390.390.390.440.440.450.450.420.421331334904900.320.320.320.320.240.240.240.240.280.281331334914910.430.430.430.430.430.430.450.450.440.441331334924920.360.360.360.360.400.400.410.410.390.391331334934930.370.370.370.370.360.360.370.370.370.371331334944940.130.130.140.140.100.100.110.110.130.131961964954950.140.140.160.160.110.110.120.120.140.141961964974970.290.290.310.310.300.300.320.320.310.314734734984980.150.150.160.160.130.130.140.140.150.154734734994990.200.200.210.210.180.180.190.190.200.20473473

Claims (35)

1. An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof, which consists of 15 to 22 nucleotides and is complementary to a nucleic acid comprising: from the base sequence of SEQ ID NO. 471, 1 st to 84 th, 142 th to 168 th, 197 th to 224 th, 286 th to 317 th, 324 th to 370 th, 391 th to 434 th, 519 th to 540 th, 623 th to 643 th, 690 th to 780 th, 824 th to 855 th, 860 th to 897 th, 948 th to 987 th, 1044 th to 1072 th, 1125 th to 1174 th, 1181 th to 1213 th, 1228 th to 1255 th, 1265 th to 1327 th, 1334 th to 1356 th, 1416 th to 1440 th, 1447 th to 1631 th, 1638 th to 1667 th, 1705 th to 1705 th, 1748 th to 1823 th, 1838 th to 1861 th, and 1870 th at least 15 consecutive regions in the group consisting of 1920 to 1941, 2000 to 2040, 2047 to 2075, 2086 to 2120, 2129 to 2187, 2194 to 2415, 2451 to 2497, 2592 to 2759, 2766 to 2870, 2928 to 2948, 2955 to 2989, 3021 to 3086, 3133 to 3209, 3217 to 3284, 3295 to 3350, 3384 to 3436, 3562 to 3771, 3858 to 3905, 401 to 4039, 4067 to 4134, 4170 to 39332, 4241 to 4283 and 4286 to 4355 are present.

2. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 1, which is complementary to a nucleic acid comprising: from the base sequence of SEQ ID NO. 471, from 1 st to 69 th, from 331 st to 363 st, from 398 th to 427 th, from 697 th to 773 th, from 867 th to 890 th, from 955 th to 980 th, from 1132 to 1167 th, from 1272 to 1320 th, from 1454 to 1624 th, from 1682 to 1705 th, from 1748 to 1816 th, from 1877 to 1906 th, from 2007 to 2033 th, from 2093 to 2113 nd, from 2136 to 2180 th, from 2201 to 2408 th, from 2458 to 2490 th at least 15 consecutive bases in the target region of the group consisting of 2599 to 2752, 2773 to 2863, 2962 to 2982, 3028 to 3079, 3140 to 3202, 3224 to 3277, 3302 to 3343, 3391 to 3429, 3569 to 3764, 3865 to 3898, 3938 to 4032, 4074 to 4127, 4177 to 4225, 4248 to 4276, and 4293 to 4355.

3. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 1, which is complementary to a nucleic acid comprising: from the base sequence of SEQ ID NO. 471, from 14 th to 33 rd, 34 th to 53 rd, 54 th to 73 rd, 148 th to 167 th, 397 th to 432 th, 723 th to 742 th, 747 th to 778 th, 965 th to 984 th, 1127 th to 1146 th, 1148 th to 1173 th, 1182 nd to 1213 th, 1228 th to 1254 th, 1270 th to 1308 th, 1484 th to 1564 th, 1578 th to 1629 th, 1686 th to 1705 th, 1748 th to 1767 th, 1768 th to 1787 th, 1794 th to 1813 th, 1870 th to 1913 th, 2015 th to 2034 th, 2086 th to 2118 th, 2129 th to 2148 th, and 2151 st to 2151 st at least 15 consecutive bases in the group consisting of 2206 to 2225, 2239 to 2272, 2287 to 2336, 2337 to 2373, 2387 to 2406, 2598 to 2757, 2775 to 2809, 2826 to 2866, 2959 to 2982, 3032 to 3051, 3052 to 3071, 3136 to 3155, 3168 to 3187, 3188 to 3207, 3232 to 3270, 3298 to 3344, 3408 to 3427, 3563 to 3582, 3590 to 3728, 3739 to 3769, 3896, 3949 to 4030 and 4170 are located in the target region.

4. An antisense oligonucleotide according to claim 3, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to a nucleic acid comprising: from the base sequence of SEQ ID NO. 471, from 14 th to 33 rd, 34 th to 53 rd, 54 th to 73 rd, 148 th to 167 th, 397 th to 416 th, 398 th to 417 th, 399 th to 418 th, 400 th to 419 th, 401 rd to 420 th, 402 th to 421 th, 403 th to 422 th, 404 th to 423 th, and, 405 to 424 bits, 407 to 426 bits, 408 to 427 bits, 413 to 432 bits, 723 to 742 bits, 747 to 766 bits, 756 to 775 bits, 759 to 778 bits, 965 to 984 bits, 1127 to 1146 bits, 1148 to 1167 bits, 1151 to 1170 bits, 1154 to 1173 bits, 1182 to 1201 bits, 1185 to 1204 bits, 1188 to 1207, 1191 to 1210, 1194 to 1213, 1228 to 1247, 1231 to 1250, 1235 to 1254, 1270 to 1289, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1506 to 1525, 1517 to 1536, 1531 to 1550, 1545 to 1564, 1578 to 1597, 1579 to 1598, 1580 to 1599, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1586 to 1605, 1587 to 1606, 1588 to 1607, 1589 to 1608, 1591 to 1610, 1592 to 1611, 1593 to 1612, 1594 to 1613, 1595 to 1614, 1596 to 1615, 1597 to 1616, 1598 to 1617, 1599 to 1618, 1600 to 1619, 1601 to 1620, 1602 to 1621, 1603 to 1622, 1604 to 1623, 1605 to 1624, 1607 to 1626, and, From 1610 to 1629, from 1686 to 1705, from 1748 to 1767, from 1768 to 1787, from 1794 to 1813, from 1870 to 1889, from 1871 to 1890, from 1874 to 1893, from 1877 to 1896, from 1878 to 1897, from 1879 to 1898, from 1880 to 1899, from 1881 to 1900, from 1882 to 1901, from 1883 to 1902, 1884 to 1903, 1885 to 1904, 1886 to 1905, 1887 to 1906, 1889 to 1908, 1894 to 1913, 2015 to 2034, 2086 to 2105, 2093 to 2112, 2094 to 2113, 2097 to 2116, 2099 to 2118, 2129 to 2148, 2151 to 2170, 2165 to 2184, 2206 th to 2225 th, 2239 th to 2258 th, 2253 rd to 2272 th, 2287 th to 2306 th, 2301 th to 2320 th, 2317 th to 2336 th, 2337 th to 2356 th, 2354 th to 2373 th, 2387 th to 2406 th, 2598 th to 2617 th, 2613 rd to 2632 th, 2614 th to 2633 th, 2615 th to 2634 th, 2616 th to 2635 th, 2617 th to 2636 th, 2618 to 2637, 2619 to 2638, 2620 to 2639, 2621 to 2640, 2622 to 2641, 2623 to 2642, 2624 to 2643, 2625 to 2644, 2626 to 2645, 2627 to 2646, 2628 to 2647, 2629 to 2648, 2630 to 2649, 2631 to 2650, 2651, 2633 to 2652, 2634 to 2653, 2635 to 2654, 2636 to 2655, 2637 to 2656, 2638 to 2657, 2639 to 2658, 2640 to 2659, 2641 to 2660, 2642 to 2661, 2643 to 2662, 2644 to 2663, 2645 to 2664, 2646 to 2665, 2647 to 2666, 2648 to 2667, 2649 to 2668, 2663 to 2682, 2672 to 2691, 2673 to 2692, 2674 to 2693, 2675 to 2694, 2676 to 2695, 2677 to 2696, 2678 to 2697, 2679 to 2698, 2680 to 2699, 2681 to 2700, 2682 to 2701, 2683 to 2702, 2684 to 2703, 2685 to 2704, 2686 to 2705, 2687 to 2706, 2688 to 2707, 2689 to 2708, 2690 to 2709, 2691 to 2710, 2692 to 2711, 2693 to 2712, 2694 to 2713, 2695 to 2714, 2696 to 2715, 2697 to 2716, 2698 to 2717, 2699 to 2718, 2700 to 2719, 2701 to 2720, 2702 to 2721, 2703 to 2722, 2704 to 2723, 2705 to 2724, 2706 to 2725, 2707 to 2726, 2708 to 2727, 2709 to 2728, 2710 to 2729, 2711 to 2730, 2712 to 2731, 2713 to 2732, 2714 to 2733, 2715 to 2734, 2716 to 2735, 2717 to 2736, 2718 to 2737, 2719 to 2738, 2720 to 2739, 2721 to 2740, 2722 to 2741, 2723 to 2742, 2724 to 2743, 2725 to 2744, 2726 to 2745, 2728 to 2747, and, 2729 to 2748, 2730 to 2749, 2731 to 2750, 2732 to 2751, 2733 to 2752, 2738 to 2757, 2775 to 2794, 2790 to 2809, 2826 to 2845, 2827 to 2846, 2828 to 2847, 2829 to 2848, 2830 to 2849, 2831 to 2850, 2832 to 2851, 2833 to 2852, 2834 to 2853, 2835 to 2854, 2836 to 2855, 2837 to 2856, 2838 to 2857, 2839 to 2858, 2840 to 2859, 2841 to 2860, 2842 to 2861, 2843 to 2862, 2844 to 2863, 2847 to 2866, 2959 to 2978, 2962 to 2981, 2963 to 2982, 3032 to 3051, 3052 to 3071, 3136 to 3155, 3168 to 3187, 3188 to 3207, 3232 to 3251, 3251 to 3270, 3298 to 3317, 3302 to 3321, 3303 to 3322, 3304 to 3323, 3305 to 3324, 3306 to 3325, 3307 to 3326, 3308 to 3327, 3309 to 3328, 3310 to 3329, 3311 to 3330, 3312 to 3331, 3313 to 3332, 3314 to 3333, 3315 to 3334, 3316 to 3335, 3317 to 3336, 3318 to 3337, 3319 to 3338, 3320 to 3339, 3321 to 3340, 3322 to 3341, 3323 to 3342, 3324 to 3343, 3325 to 3344, 3408 to 3427, 3563 to 3582, 3590 to 3609, 3608 to 3627, 3617 to 3636, 3618 to 3637, 3619 to 3638, 3620 to 3639, 3621 to 3640, 3622 to 3641, 3623 to 3642, 3624 to 3643, 3625 to 3644, 3626 to 3645, 3627 to 3646, 3628 to 3647, 3629 to 3648, 3630 to 3649, 3631 to 3650, 3632 to 3651, 3633 to 3652, 3634 to 3653, 3635 to 3654, 3636 to 3655, 3637 to 3656, 3638 to 3657, 3639 to 3658, 3640 to 3659, 3641 to 3660, 3642 to 3661, 3643 to 3662, 3644 to 3663, 3645 to 3664, 3646 to 3665, 3647 to 3666, 3648 to 3667, 3649 to 3668, 3650 to 3669, 3651 to 3670, 3652 to 3671, 3653 to 3672, 3654 to 3673, 3671 to 3690, 3672 to 3691, 3673 to 3692, 3674 to 3693, 3675 to 3694, 3676 to 3695, 3677 to 3696, 3678 to 3697, 3679 to 3698, 3680 to 3699, 3681 to 3700, 3682 to 3701, 3683 to 3702, 3684 to 3703, 3685 to 3704, and, 3686 to 3705, 3687 to 3706, 3688 to 3707, 3689 to 3708, 3690 to 3709, 3691 to 3710, 3692 to 3711, 3693 to 3712, 3694 to 3713, 3695 to 3714, 3696 to 3715, 3697 to 3716, 3698 to 3717, 3699 to 3718, 3700 to 3719, 3701 to 3720, 3702 to 3721, 3703 to 3722, 3704 to 3723, 3705 to 3724, 3706 to 3725, 3707 to 3726, 3708 to 3727, 3709 to 3728, 3739 to 3758, 3740 to 3759, 3741 to 3760, 3742 to 3761, 3743 to 3762, 3744 to 3763, 3745 to 3764, 3750 to 3769, 3877 to 3896, 3949 to 3968, 3964 to 3983, 3965 to 3984, 3966 to 3985, 3967 to 3986, 39968 to 3987, 3969 to 3998, 3970 to 3989, 3971 to 3990, 392 to 39991, 3973 to 3992, 3974 to 3993, and, 3975 to 3994, 3976 to 3995, 3978 to 3997, 3980 to 3999, 3991 to 3998, 3991 to 4000, 3993 to 4002, 3994 to 4003, 3995 to 4004, 3996 to 4005, 3987 to 4006, 4008 to 4007, 3989 to 4008, 3990 to 4019, 3992 to 4011, 3993 to 4012, 3995 to 4014, 3997 to 4016, 3998 to 4017, 3999 to 4018, 4011 to 4030, 4170 to 4189, 4173 to 4192, 4176 to 4195, 4177 to 4196, 4178 to 4197, 4179 to 4198, 4180 to 4199, 4181 to 4200, 4182 to 4201, 4183 to 4202, 4184 to 4203, 4185 to 4204, 4186 to 4205, 4187 to 4206, 4188 to 4207, 4189 to 4208, 4190 to 4209, 4191 to 4210, 4192 to 4211, at least 15 consecutive bases in the target region of the group consisting of 4193 to 4212, 4194 to 4213, 4195 to 4214, 4196 to 4215, 4197 to 4216, 4198 to 4217, 4199 to 4218, 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224, and 4206 to 4225.

5. An antisense oligonucleotide according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to a nucleic acid comprising: from the base sequence of SEQ ID NO. 471, from 14 th to 33 rd, 34 th to 53 rd, 398 th to 427 th, 723 th to 742 th, 747 th to 766 th, 1148 th to 1167 th, 1289 th to 1308 th, 1484 th to 1564 th, 1578 th to 1624 th, 1686 th to 1705 th, 1748 th to 1767 th, 1768 th to 1787 th, 1794 th to 1813 th, 1877 th to 1906 th, 2093 th to 2113 th, 2151 th to 2170 th, 2206 th to 2225 th, 2239 th to 2272 th, 2287 th to 2336 th at least 15 consecutive bases in the target region of the group consisting of 2337 th to 2373 th, 2387 th to 2406 th, 2613 rd to 2752 th, 2775 th to 2809 th, 2826 th to 2863 th, 2962 th to 2982 th, 3032 nd to 3051 th, 3052 nd to 3071 th, 3168 th to 3187 th, 3232 th to 3270 th, 3302 nd to 3343 th, 3408 th to 3427 th, 3590 th to 3728 th, 3739 th to 3764 th, 3877 th to 3896 th, 3949 th to 4030 th and 4177 th to 4225 th.

6. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 5, which is complementary to a nucleic acid comprising: from the base sequence of SEQ ID NO. 471, from 14 th to 33 rd, 34 th to 53 rd, 398 th to 417 th, 399 th to 418 th, 400 th to 419 th, 401 rd to 420 th, 402 th to 421 th, 403 rd to 422 th, 404 th to 423 th, 405 th to 424 th, 406 th to 425 th, 407 th

426 Th, 408 th to 427 th, 723 th to 742 th, 747 th to 766 th and 1148 th

1167, 1289 To 1308, 1484 to 1503, 1488 to 1507

Bit, 1491-1510, 1493-1512, 1506-1525 and 1517

Bits 1536, 1531 to 1550, 1545 to 1564, 1578 to 1597

Position 1579 to 1598, 1580 to 1599, 1581 to 1600, 1582

From position 1601 to position 1583 to position 1602, from position 1584 to position 1603, from position 1585 to position 1604

Position 1586 to 1605, 1587 to 1606, 1588 to 1607, 1589

Bits 1608, 1590 to 1609, 1591 to 1610, 1592 to 1611

Bit, 1593 to 1612, 1594 to 1613, 1595 to 1614, 1596

From position 1615, from position 1597 to position 1616, from position 1598 to position 1617, from position 1599 to position 1618

Bits 1600 to 1619, 1601 to 1620, 1602 to 1621, 1603

Bits 1622, 1604 to 1623, 1605 to 1624, 1686 to 1705

Bits 1748 to 1767, 1768 to 1787, 1794 to 1813, 1877

1896 Th, 1878 th to 1897 th, 1879 th to 1898 th, 1880 th to 1899 th

Bit, 1881 th to 1900 th bit, 1882 th to 1901 th bit, 1883 th to 1902 th bit, 1884 th bit

Position 1903, 1885 to 1904, 1886 to 1905, 1887 to 1906

Bit, 2093 bit to 2112 bit, 2094 bit to 2113 bit, 2151 bit to 2170 bit, 2206

Bits 2225, 2239 and 2258, 2253 and 2272, 2287 and 2306

Bits 2301 to 2320, 2317 to 2336, 2337 to 2356, 2354

Bits 2373, 2387, 2406, 2613, 2632, 2614, 2633

Bits 2615 to 2634, 2616 to 2635, 2617 to 2636, 2618

Bits 2637, 2619 and 2638, 2620 and 2639, 2621 and 2640

Positions 2622 to 2641, positions 2623 to 2642, positions 2624 to 2643, and positions 2625

2644, 2626 To 2645, 2627 to 2646, 2628 to 2647)

Bits 2629 to 2648, 2630 to 2649, 2631 to 2650, 2632

Bits 2651, 2633, 2652, 2634, 2653, 2635, 2654

Bits 2636 to 2655, 2637 to 2656, 2638 to 2657, 2639

Bits 2658, 2640 to 2659, 2641 to 2660, 2642 to 2661

Bits 2643 to 2662, 2644 to 2663, 2645 to 2664, 2646

Positions 2665, 2647, 2666, 2648, 2667, 2649 and 2668

Bits 2663 to 2682, 2672 to 2691, 2673 to 2692, 2674

2693 Th, 2675 th to 2694 th, 2676 th to 2695 th, 2677 th to 2696 th

Bits 2678 to 2697, 2679 to 2698, 2680 to 2699, 2681

Position 2700, 2682 to 2701, 2683 to 2702, 2684 to 2703

Position 2685 to 2704, 2686 to 2705, 2687 to 2706, 2688

Position 2707, 2689 to 2708, 2690 to 2709, 2691 to 2710

Position 2692 to 2711, 2693 to 2712, 2694 to 2713, 2695

Position 2714, 2696, 2715, 2697, 2716, 2698, 2717

Position 2699 to 2718, 2700 to 2719, 2701 to 2720, 2702

Position 2721, 2703 position 2722 position, 2704 position 2723 position, 2705 position 2724 position

Position, 2706 th to 2725 th, 2707 th to 2726 th, 2708 th to 2727 th, 2709 th

Position 2728, position 2710 to position 2729, position 2711 to position 2730, position 2712 to position 2731

Position, 2713 rd to 2732 rd, 2714 th to 2733 rd, 2715 th to 2734 th, 2716 th

Position 2735, position 2717 to position 2736, position 2718 to position 2737, position 2719 to position 2738

Position, 2720 th to 2739 th positions, 2721 st to 2740 th positions, 2722 nd to 2741 st positions, 2723 th positions

Position 2742, position 2724 to position 2743, position 2725 to position 2744, position 2726 to position 2745

Position, 2727 th to 2746 th, 2728 th to 2747 th, 2729 th to 2748 th, 2730 th

Position 2749, position 2731, position 2750, position 2732, position 2751, position 2733, position 2752

Position 2775 to 2794, 2790 to 2809, 2826 to 2845 and 2827

2846, 2828 To 2847, 2829 to 2848, 2830 to 2849

2831 St to 2850 th, 2832 nd to 2851 st, 2833 nd to 2852 nd, 2834 th

2853, 2835, 2854, 2836, 2855, 2837, 2856

2838 To 2857, 2839 to 2858, 2840 to 2859, 2841

2860 Th, 2842 th to 2861 th, 2843 th to 2862 th, 2844 th to 2863 th

Bit 2962 to 2981, 2963 to 2982, 3032 to 3051, 3052

From position 3071, from position 3168 to position 3187, from position 3232 to position 3251, from position 3251 to position 3270

Bits 3302 to 3321, 3303 to 3322, 3304 to 3323, 3305

Bits 3324, 3306 and 3325, 3307 and 3326, 3308 and 3327

Bits 3309 to 3328, 3310 to 3329, 3311 to 3330, 3312

Bits 3313 to 3332, 3314 to 3333, 3315 to 3334

Bits 3316 to 3335, 3317 to 3336, 3318 to 3337, 3319

Bits 3338, 3320 to 3339, 3321 to 3340, 3322 to 3341

Bit, 3323 th to 3342 th, 3324 th to 3343 th, 3408 th to 3427 th, 3590 th

Bits 3609, 3608 to 3627, 3617 to 3636, 3618 to 3637

3619 St to 3638 st, 3620 th to 3639 st, 3621 st to 3640 st, 3622 nd

3641 St, 3623 st to 3642 nd, 3624 st to 3643 st, 3625 st to 3644 st

3626 To 3645, 3627 to 3646, 3628 to 3647, 3629

3648, 3630 To 3649, 3631 to 3650, 3632 to 3651

Bit 3633 to 3652, 3634 to 3653, 3635 to 3654, 3636

3655, 3637 To 3656, 3638 to 3657, 3639 to 3658

Bit 3640 to 3659, 3641 to 3660, 3642 to 3661, 3643

3662, 3644 To 3663, 3645 to 3664, 3646 to 3665

3647-3666, 3648-3667, 3649-3668 And 3650

3669, 3651, 3670, 3652, 3671, 3653 And 3672

3654 Th to 3673 th, 3671 th to 3690 th, 3672 nd to 3691 th, 3673 th

3692 Th, 3674 th to 3693 th, 3675 th to 3694 th, 3676 th to 3695 th

3677 To 3696, 3678 to 3697, 3679 to 3698, 3680

3699 Th, 3681 th to 3700 th, 3682 th to 3701 th, 3683 th to 3702 th

Bit 3684 to 3703, 3685 to 3704, 3686 to 3705, 3687

From position 3706, 3688 to 3707, 3689 to 3708, 3690 to 3709

From 3691 to 3710, from 3692 to 3711, from 3693 to 3712, from 3694 to 3713, from 3695 to 3714, from 3696 to 3715, from 3697 to 3716, from 3698 to 3717, from 3699 to 3718, from 3700 to 3719, from 3701 to 3720, from 3702 to 3721, from 3703 to 3722, from 3704 to 3723, from 3705 to 3724, 3706 to 3725, 3707 to 3726, 3708 to 3727, 3709 to 3728, 3739 to 3758, 3740 to 3759, 3741 to 3760, 3742 to 3761, 3743 to 3762, 3744 to 3763, 3745 to 3764, 387 to 3896, 3949 to 3968, 3964 to 3983, 3965 to 3984, 3966 to 3995, 3967 to 3996, 3968 to 3987, 3969 to 3998, 3970 to 3989, 3971 to 3990, 3972 to 3991, 3974 to 3993, 3975 to 3994, 3976 to 3996, 3977 to 3996, 397 to 3996, 3978 to 3997, 399 to 3998, 3980 to 3999, 3981 to 4000, 3982 to 4001, 3983 to 4002, 3984 to 4003, 3985 to 4004, 3986 to 4005, 3987 to 4006, 3998 to 4007, 3989 to 4008, 3990 to 4009, 3991 to 4010, 3992 to 4011, 3993 to 4012, 3995 to 4014, 3996 to 4015, 3998 to 4017, 3999 to 4018, 4011 to 4030, 4177 to 4196, 4178 to 4197, 4179 to 4198, 4180 to 4199, 4181 to 4200, 4182 to 4201, 4183 to 4202, 4184 to 4203, 4185 to 4204, 4186 to 4205, 4187 to 4206, 4188 to 4207, 4189 to 4208, 4190 to 4209, 4191 to 4210, 4192 to 4211, 4193 to 4212, 4194 to 4213, 4195 to 4214, 4196 to 4215, 4197 to 4216, 4198 to 4217, 4199 to 4218, 0 to 4219, 4201 to 4220, at least 15 consecutive bases in the target region of the group consisting of 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224, and 4206 to 4225.

7. An antisense oligonucleotide according to claim 3, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is complementary to a nucleic acid comprising: from the base sequence of SEQ ID NO. 471, from 14 th to 33 rd, 34 th to 53 th, 54 th to 73 th, 148 th to 167 th, 397 th to 432 th, 747 th to 778 th, 965 th to 984 th, 1127 th to 1146 th, 1148 th to 1173 th, 1182 nd to 1213 th, 1228 th to 1254 th, 1270 th to 1308 th, 1484 th to 1564 th, 1578 th to 1629 th, 1686 th to 1705 th, 1748 th to 1767 th, 1768 th to 1787 th, 1794 th to 1813 th, 1870 th to 1913 th, 2015 th to 2034 th, 2086 th to 8 th, 2129 th to 2148 th, 2170 th to 2170 th, 226 th to 2156 th, and 2287 th to 2335 th at least one of the target groups consisting of 2337 to 2373, 2387 to 2406, 2598 to 2632, 2633 to 2668, 2672 to 2691, 2699 to 2757, 2775 to 2809, 2826 to 2866, 2959 to 2978, 3032 to 3051, 3052 to 3071, 3136 to 3155, 3168 to 3187, 3188 to 3207, 3232 to 3270, 3298 to 3317, 3325 to 3344, 3408 to 3427, 3590 to 3690, 3691 to 3728, 3739 to 3769, 387 to 3896, 3949 to 3983, and 4198 to 4070.

8. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 7, which is complementary to a nucleic acid comprising: from the group consisting of the 14 th to 33 rd, 34 th to 53 rd, 54 th to 73 rd, 148 th to 167 th, 397 th to 416 th, 413 th to 432 th, 747 th to 766 th, 756 th to 775 th, 759 th to 778 th, 965 th to 984 th, 1127 th to 1146 th, 1148 th to 1167 th, and the like of the base sequence of SEQ ID NO 471, 1151 to 1170, 1154 to 1173, 1182 to 1201, 1185 to 1204, 1188 to 1207, 1191 to 1210, 1194 to 1213, 1228 to 1247, 1231 to 1250, 1235 to 1254, 1270 to 1289, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1517 to 1536, 1531 to 1550, 1545 to 1564, 1578 to 1597, 1586 to 1605, 1589 to 1608, 1592 to 1611, 1595 to 1614, 1598 to 1617, 1601 to 1620, 1604 to 1623, 1607 to 1626, 1610 to 1629, 1686 to 1705, 1748 to 1767, 1768 to 1787, 1794 to 1813, 1870 to 1889, 1871 to 1890, 1874 to 1893, 1877 to 1896, 1880 to 1899, 1883 to 1902, 1886 to 1905, 1889 to 1908, 1894 to 1913, 2015 to 2034, 2086 to 2105, 2097 to 2116, 2099 to 2118, 2129 to 2148, 2151 to 2170, 2206 to 2225, 2239 to 2258, 2253 to 2272, 2287 to 2306, 2301 to 2320, 2317 to 2336, 2354 to 2373, 2387 to 2406, 2598 to 2617, 2613 to 2632, 2633 to 2652, 2649 to 2668, 2672 to 2691, 2699 to 2718, 2702 to 2721, 2705 to 2724, 2708 to 2727, 2711 to 2730, 2714 to 2733, 2717 to 2736, 2720 to 2739, 2723 to 2742, 2726 to 2745, 2729 to 2748, 2738 to 2757, 2794 to 2794, 2845 to 2829 to 2848, 2832 to 2851, 2835 to 2854, 2838 to 2857, 2841 to 2860, 2847 to 2866, 2959 to 2978, 3032 to 3051, 3052 to 3071, 3136 to 3155, 3168 to 3187, 32088 to 3207, 3232 to 3251, 3251 to 3270, 3298 to 3317, 3325 to 3344, 3408 to 3427, 3590 to 3609, 3608 to 3627, 3617 to 3636, 3635 to 3654, 3654 to 3673, 3671 to 3690, 3691 to 3710, 3709 to 3728, 3739 to 3758, 3750 to 3769, At least 15 consecutive bases in a target region of the group consisting of 3877 th to 3896 th, 3949 th to 3968 th, 3964 th to 3983 th, 3984 th to 4003 th, 3999 th to 4018 th, 4011 st to 4030 th, 4170 th to 4189 th, 4173 th to 4192 th, 4176 th to 4195 th and 4179 th to 4198 th.

9. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 5 or 7, which is complementary to a nucleic acid comprising: from the base sequence of SEQ ID NO. 471, from 14 th to 33 rd, 34 th to 53 rd, 747 th to 766 th, 1148 th to 1167 th, 1289 th to 1308 th, 1484 th to 1564 th, 1578 th to 1623 th, 1686 th to 1705 th, 1748 th to 1767 th, 1768 th to 1787 th, 1794 th to 1813 th, 1877 th to 1905 th, 2151 th to 2170 th, 2206 th to 2225 th, 2239 th to 2272 th, 2287 th to 2336 th, 2337 th to 2373 th, 2387 th to 2406 th, 2613 rd to 2632 th at least 15 consecutive bases in the target region of the group consisting of 2633 to 2668, 2672 to 2691, 2699 to 2748, 2775 to 2809, 2826 to 2860, 3032 to 3051, 3052 to 3071, 3168 to 3187, 3232 to 3270, 3408 to 3427, 3590 to 3690, 3691 to 3728, 3739 to 3758, 3877 to 3896, 3949 to 3983, 3984 to 4030, and 4179 to 4198.

10. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 9, which is complementary to a nucleic acid comprising: from the group consisting of position 14 to position 33, position 34 to position 53, position 747 to position 766, position 1148 to position 1167, position 1289 to position 1308, position 1484 to position 1503, position 1488 to position 1507, position 1491 to position 1510, position 1493 to position 1512, position 1506 to position 1525, position 1517 to position 1536, and the nucleotide sequence of SEQ ID NO 471, 1531 to 1550, 1545 to 1564, 1578 to 1597, 1586 to 1605, 1589 to 1608, 1592 to 1611, 1595 to 1614, 1598 to 1617, 1601 to 1620, 1604 to 1623, 1686 to 1705, 1748 to 1767, 1768 to 1787, 1794 to 1813, 1877 to 1896, 1880 to 1899, 1883 to 1902, 1886 to 1905, 2151 to 2170, 2206 to 2225, 2239 to 2258, 2253 to 2272, 2287 to 2306, 2301 to 2320, 2317 to 2336, 2354 to 2373, 2387 to 2406, 2613 to 2632, 2633 to 2652, 2649 to 2668, 2672 to 2691, 2699 to 2718, 2702 to 2721, 2705 to 2724, 2708 to 2727, 2711 to 2730, 2714 to 2733, 2717 to 2736, 2720 to 2739, 2723 to 2742, 2726 to 2745, 2729 to 2748, 2775 to 2794, 2790 to 2809, and, 2826 to 2845, 2829 to 2848, 2832 to 2851, 2835 to 2854, 2838 to 2857, 2841 to 2860, 3032 to 3051, 3052 to 3071, 3168 to 3187, 3232 to 3251, 3251 to 3270, 3408 to 3427, 3590 to 3609, 3608 to 3627, 3617 to 3636, at least 15 consecutive bases in a target region of the group consisting of 3635 to 3654, 3654 to 3673, 3671 to 3690, 3691 to 3710, 3709 to 3728, 3739 to 3758, 3877 to 3896, 3949 to 3968, 3964 to 3983, 3984 to 4003, 3999 to 4018, 4011 to 4030, and 4179 to 4198.

11. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 7, which is complementary to a nucleic acid comprising: at least 15 consecutive bases in the target region selected from the group consisting of 1598 to 1626, 1870 to 1890, 2097 to 2116, 2711 to 2736, 2841 to 2860 and 4170 to 4198 of the base sequence of SEQ ID NO. 471.

12. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 7 or 8, which is complementary to a nucleic acid comprising: at least 15 consecutive bases in the target region selected from the group consisting of 1598 th to 1617 th, 1604 th to 1623 th, 1607 th to 1626 th, 1870 th to 1889 th, 1871 th to 1890 th, 2097 th to 2116 th, 2711 th to 2730 th, 2714 th to 2733 th, 2717 th to 2736 th, 2841 th to 2860 th, 4170 th to 4189 th, 4173 th to 4192 th and 4179 th to 4198 th of the base sequence of SEQ ID NO 471.

13. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to any one of claims 1-12, which is complementary to a nucleic acid comprising at least 20 consecutive bases of the target region.

14. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 3 or 4, comprising:

(i) A base sequence selected from the group consisting of SEQ ID Nos. 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158 and 160 to 464;

(ii) 1 or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NO.1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158 and 160 to 464; or (b)

(Iii) A base sequence having a sequence identity of 90% or more with respect to a base sequence selected from the group consisting of SEQ ID Nos. 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158 and 160 to 464.

15. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 5 or 6, comprising:

(i) A base sequence selected from the group consisting of SEQ ID Nos. 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163 to 464;

(ii) 1 or more bases are added, deleted or substituted in a base sequence selected from the group consisting of SEQ ID NO.1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163 to 464; or (b)

(Iii) A base sequence having a sequence identity of 90% or more with respect to a base sequence selected from the group consisting of SEQ ID Nos. 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163 to 464.

16. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 7 or 8, comprising:

(i) A base sequence selected from the group consisting of SEQ ID NOS 1～4、6、8、9、11、14～24、26、29、31～37、39～50、52～60、66～67、73～75、79～82、86～89、92～111、115～118、120～136、138～145、147～158 and 160 to 163;

(ii) A base sequence obtained by adding, deleting or replacing 1 or several bases to a base sequence selected from the group consisting of SEQ ID NO. 1～4、6、8、9、11、14～24、26、29、31～37、39～50、52～60、66～67、73～75、79～82、86～89、92～111、115～118、120～136、138～145、147～158 and 160 to 163; or (b)

(Iii) A base sequence having a sequence identity of 90% or more with respect to a base sequence selected from the group consisting of SEQ ID NOS 1～4、6、8、9、11、14～24、26、29、31～37、39～50、52～60、66～67、73～75、79～82、86～89、92～111、115～118、120～136、138～145、147～158 and 160 to 163.

17. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 9 or 10, comprising:

(i) A base sequence selected from the group consisting of SEQ ID Nos. 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163;

(ii) A base sequence obtained by adding, deleting or replacing 1 or several bases to a base sequence selected from the group consisting of SEQ ID NO.1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163; or (b)

(Iii) A base sequence having a sequence identity of 90% or more with respect to a base sequence selected from the group consisting of SEQ ID Nos. 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158 and 163.

18. An antisense oligonucleotide according to claim 11 or 12, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i) A base sequence selected from the group consisting of SEQ ID NOS 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161 and 163;

(ii) A base sequence obtained by adding, deleting or substituting 1 or several bases to a base sequence selected from the group consisting of SEQ ID NO. 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161 and 163; or (b)

(Iii) A base sequence having a sequence identity of 90% or more with respect to a base sequence selected from the group consisting of SEQ ID NOS.98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161 and 163.

19. An antisense oligonucleotide according to claim 11 or 12, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i) A base sequence selected from the group consisting of SEQ ID NOS.21 to 222, 233, 234 and 350 to 355;

(ii) A base sequence obtained by adding, deleting or substituting 1 or several bases to a base sequence selected from the group consisting of SEQ ID NO. 21, 164 to 222, 233, 234 and 350 to 355; or (b)

(Iii) A base sequence having a sequence identity of 90% or more with respect to a base sequence selected from the group consisting of SEQ ID NOS.21 to 222, 233, 234 and 350 to 355.

20. An antisense oligonucleotide according to claim 11 or 12, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:

(i) A base sequence selected from the group consisting of sequence numbers 170, 177, 196, 199, and 221;

(ii) A base sequence obtained by adding, deleting or substituting 1 or several bases to a base sequence selected from the group consisting of SEQ ID NOS.170, 177, 196, 199 and 221; or (b)

(Iii) A base sequence having a sequence identity of 90% or more with respect to a base sequence selected from the group consisting of SEQ ID NOS.170, 177, 196, 199 and 221.

21. The antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof according to any one of claims 14 to 20, which comprises the base sequence of (i).

22. An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof, which consists of 15 to 22 nucleotides and is complementary to a nucleic acid comprising: at least one of the groups consisting of nucleotides 468 to 487, 474 to 493, 583 to 602, 586 to 605, 619 to 638, 770 to 789, 774 to 793, 775 to 794, 778 to 797, 804 to 823, 851 to 870, 1160 to 1179, 1162 to 1181, 1170 to 1189, 1173 to 1192, 1205 to 1224, 1216 to 1225, 1217 to 1236, 1219 to 1238, 1381 to 19020, 1818 to 1837, position 1925 to 1925, position 1924 to 1934, and position 192 to 1936 to 19315 in the base sequence of SEQ ID NO. 471.

23. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 22, comprising:

(i) A base sequence selected from the group consisting of SEQ ID NOS.7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146 and 159;

(ii) A base sequence obtained by adding, deleting or replacing 1 or several bases to a base sequence selected from the group consisting of SEQ ID NO. 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146 and 159; or (b)

(Iii) A base sequence having a sequence identity of 90% or more with respect to a base sequence selected from the group consisting of SEQ ID Nos. 7,10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146 and 159.

24. The antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 23, which comprises the base sequence of (i).

25. The antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof according to any one of claims 1 to 24, wherein the antisense oligonucleotide consists of 20 nucleotides.

26. An antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof according to any one of claims 1-25, wherein the sugar moiety and/or phosphate bond moiety of at least 1 nucleotide constituting the oligonucleotide is modified.

27. The antisense oligonucleotide or a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 26, wherein the antisense oligonucleotide is a spacer oligonucleotide comprising a middle spacer region and 2 flanking regions (5 'flanking region and 3' flanking region) adjacent to the 5 'terminal side and 3' terminal side of the spacer region.

28. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 27, wherein all bonds between nucleosides are phosphorothioate bonds.

29. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 27, wherein one or more of the bond between the nucleoside at position 2 and 3, the bond between the nucleoside at position 3 and 4, and the bond between the nucleoside at position 4 and 5 from the 5 'side of the 5' flanking region is a phosphodiester bond, and/or one or more of the bond between the nucleoside at position 1 and 2, the bond between the nucleoside at position 2 and 3, and the bond between the nucleoside at position 3 and 4 from the 5 'side of the 3' flanking region is a phosphodiester bond,

And all bonds between other nucleosides are phosphorothioate linkages.

30. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 29, wherein the bond between the nucleoside at the 2 nd and 3 rd positions and the bond between the nucleoside at the 4 th and 5 th positions from the 5 'side of the 5' flanking region are phosphodiester bonds, and/or the bond between the nucleoside at the 1 st and 2 nd positions and the bond between the nucleoside at the 3 rd and 4 th positions from the 5 'side of the 3' flanking region are phosphodiester bonds,

And all bonds between other nucleosides are phosphorothioate linkages.

31. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to claim 29, wherein the bond between the nucleoside at position 2 and 3, the bond between the nucleoside at position 3 and 4, and the bond between the nucleoside at position 4 and 5 from the 5 'side of the 5' flanking region are phosphodiester bonds, and/or the bond between the nucleoside at position 1 and 2, the bond between the nucleoside at position 2 and 3, and the bond between the nucleoside at position 3 and 4 from the 5 'side of the 3' flanking region are phosphodiester bonds,

And all bonds between other nucleosides are phosphorothioate linkages.

32. An antisense oligonucleotide according to any one of claims 27-31, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the flanking regions comprise a 2'-OMe (2' -O-CH₃) group and/or a 2'-O-MOE (2' -O-CH₂CH₂OCH₃) group.

33. A pharmaceutical composition comprising the antisense oligonucleotide of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

34. The antisense oligonucleotide or pharmaceutically acceptable salt thereof or hydrate thereof according to any one of claims 1 to 32, or the pharmaceutical composition according to claim 33, for use in the treatment and/or prevention of dentate nuclear pallidosis atrophy (DRPLA).

35. A method of treating and/or preventing dentate nucleus pallidum atrophy (DRPLA) comprising the step of administering the antisense oligonucleotide of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or the pharmaceutical composition of claim 33 or 34, to a subject.