WO2025085868A2

Movatterモバイル変換

Info

Publication number: WO2025085868A2
Application number: PCT/US2024/052143
Authority: WO
Inventors: Jeffrey ISENBERG; Hong M. Moulton; Jon MOULTON
Original assignee: RADIATION CONTROL TECHNOLOGIES Inc; Oregon State University
Current assignee: RADIATION CONTROL TECHNOLOGIES Inc; Oregon State University
Priority date: 2023-10-20
Filing date: 2024-10-18
Publication date: 2025-04-24
Anticipated expiration: 2026-04-20
Also published as: WO2025085868A3

Abstract

The present disclosure provides human-CD47-specific antisense morpholino oligonucleotides useful to reduce expression of CD47 protein, for instance in order to reduce genotoxicity secondary from chemotherapy or radiation. Methods of use of the morpholinos are also provided.

Description

Filed October 18, 2024 [0181] The CD47 morpholino decreases the effects of each of the interactions noted above, by lowering the available amount of CD47, the common mediator of the multiple injurious signals. Thus, it is the most rational and efficient means of obtaining therapeutic benefit under any circumstance. The morpholino renders primary cells, tissues, and organs CD47 “lite” to prevent and limit disease and injury such as death from genotoxic stress while preserving and enhancing immune cell actions towards cancers and while driving cancer cell killing from genotoxic stress via increased autophagy (Feliz-Mosquea et al., Breast Cancer Res Treat.172(1):69-82, 2018). IX. CD47 Morpholino Oligonucleotides [0182] A translation promiscuous CD47 morpholino that covered to some degree the murine, porcine, and human mRNA sequence of CD47 was given to adult mice followed three days later by regional radiation to the hindlimb. The morpholino-treated animals showed protection from radiation-mediated tissue destruction (Isenberg et al., Am J Pathol.2008;173: 1100–1112). Two months after, the morpholino-treated animals showed no skin or muscle injury versus control animals that had skin and muscle scarring, tissue loss, and limb contracture from secondary fibrosis. This protective effect of the morpholino was cell autonomous as cells from mice that were rendered CD47 ‘lite’ were also very resistant to radiation-mediated cell death. Even more startling, CD47 morpholino treatment maintained the colony forming capacity of bone marrow hematopoietic cells following high dose radiation (Maxhimer et al., Sci Transl Med.2009;1:3ra7). The CD47 morpholino-treated mice were rendered immune to lethal whole-body lethal radiation. These mice showed no cytopenia after whole-body radiation. This is very significant since one of the major complications of therapeutic radiation is loss of immune cells and loss of immune cell capacity. This effect contributes heavily to death after whole body radiation and lack of cancer killing by radiation. This finding also indicated that a CD47 morpholino will be beneficial in cases of accidental radiation exposure. However, in all of these prior studies it was necessary to treat with the CD47 morpholino 48 to 72 hours prior to exposure to radiation, or other genotoxic stress such as chemotherapy. The human-only CD47 morpholino can be given at the same time as the genotoxic stress. [0183] In vivo, mice given a CD47 morpholino and radiation had no tumor growth. Analysis of the tumors found increased numbers of tumor-associated macrophages, which are known to be cytotoxic to the tumors (Maxhimer et al., Sci Transl Med.2009 Oct 21;1(3):3ra7). These findings are in line with the role that TSP1-CD47 plays in suppressing immune activation and in suppressing most immune cell types including T, NK, and dendritic cells, and macrophages. Then, the CD47 morpholino oligonucleotide enhances anti-tumor immunity by protecting immune cells associated with tumors from the cytotoxic effects of ionizing radiation, and chemotherapy. Lowering of CD47 correlated with better phagocytosis (Hayes et al., J Cell Sci. 2020 Mar 6;133(5): jcs237800). Thus, immune attack of cancer does not require full blockade of CD47, as Filed October 18, 2024 current clinical CD47 antibodies do. This again validates the CD47 morpholino therapeutic strategy as the safer and multiply effective approach. The CD47 morpholino also directly kills tumor cells by dysregulating autophagy (Soto-Pantoja et al., Autophagy.8(11):1628-42, 2012) and that would trigger signaling pathways that immune cells would respond to. [0184] Separate from this, a research grade CD47 morpholino improved function and renewal of deteriorated aged human cells (Porpiglia et al., Cell Stem Cell. 2022 Dec 1;29(12):1653- 1668.e8). These data support many of the findings that have been published or therapeutic effects from a CD47 morpholino under various stressors. This is consistent with the known role we discovered for TSP1-CD47 to increase with age to limit self-renewal (Ghimire, Cells.2020 Jul 15;9(7):1695). Cancer is a primarily disease of aging. Age-related increase in CD47 is no doubt a factor that diminishes immune cell self-renewal and vitality. In this way, the CD47 morpholinos will invigorate and rejuvenate immune cells as well as protect them from genotoxic stress. [0185] Another mechanism of action of CD47 morpholino oligonucleotides is regulating tumor hypoxia through normalization of the tumor vasculature (Frazier et al., Nature Signaling Gateway. 2010). It was shown that TSP1-CD47 controlled tumor blood flow (Isenberg et al., Neoplasia. 2008;10: 886–896). More specifically, the ability of the CD47 suppressing morpholino oligonucleotides to protect non-cancer cells, tissues, and organs from radiation and chemotherapy stems from, in part, increased NO signaling (Isenberg et al., Ann Surg. 2008 May;247(5):860-8). As well, it is known now that the CD47 morpholino activates protective autophagy following radiation (Soto-Pantoja et al., Autophagy 8:1628-1642, 2012), and improves metabolic response in non-cancer cells, tissues, and organs. This protective autophagy response is evident in isolated cells and in tissues of irradiated mice. In addition, the protection afforded by the CD47 morpholino is especially marked under genotoxic stress that damages DNA. [0186] The beneficial effects of CD47 morpholino oligonucleotides are also mediated through preservation of immune cells and enhanced immune cell activity towards, and in, the tumors. This is consistent with the role TSP1-CD47 signaling has in suppressing activation of T, NK, and dendritic cells and macrophages immune cells (Kaur et al., J Immunol 2014, 193(8):3914-3924; Nath et al., Cancer Immunol Res 2019, 7(9):1547-1561; Doyen et al., J Exp Med 2003, 198(8):1277-1283). Thus, TSP1-CD47 signaling is a checkpoint on immune cells; given its high affinity, the very high affinity of the binding interaction it is likely a dominant checkpoint in many situations. Work from our team, collaborators and other groups, shows that suppressing this pathway can be leveraged to treat cancer. This raises, another advantage of morpholino oligonucleotide strategies to lower CD47. Being small in size, morpholinos do not themselves trigger auto-immune injury, that is they are not themselves immunogenic (Paraiso et al., Dev Cell. 2019, 49(4):643-650.e3), as blocking antibodies can and most certainly do trigger immune response and thus have less activity after each administration being sequestered and cleared rapidly. This is not a small advantage as use of such checkpoint blocking antibodies in individuals Filed October 18, 2024 with cancer caused type 1 insulin-dependent diabetes, a likely side-effect so to be encountered with all clinical CD47 blocking antibodies. Although, an exon skipping morpholino that promoted new protein production did alter auto-immunity in mice (Vila et al., J Pathol 2019; 248: 339–351). However, such effects have not been described in large numbers of individuals given exon skipping morpholinos for extended periods of time (Echigoya et al., Mol Ther Nucleic Acids.2015 4(2): e225). [0187] Others have used clustered regularly interspaced short palindromic repeats (CRISPR) gene editing to achieve partial CD47 suppression in tumor cells, with resulting increased macrophage killing of cancer cells (Hayes et al., BioRXiv, 2022 Sept 28, doi.org/10.1101/2022.09.27.509740). This study confirms the overall principle that partial suppression of CD47 increases cancer killing. However, CRISPER has many problems with stability of editing changes, unwanted off-target effects such as actually stimulating cancers, and is found ineffective in suppressing the target gene in many cell types. Indeed, it has been noted that CRISPR is not effective to lower CD47 in primary human cells. X. Human-Specific CD47-Targeted Morpholino Oligonucleotides [0188] Described herein is the development and functional characterization of several human- only CD47 morpholino oligonucleotides. These include translation blocking CD47-targeted morpholinos (SEQ ID NOs: 1, 3-5, 16) as well as splice blocking CD47-targeted morpholinos (SEQ ID NOs: 2, 6-15). Also described are CD47-targeted morpholinos that are each conjugated to a cell-penetrating peptide (CPP). [0189] Translation blocking morpholinos SEQ ID NO: 1 (CD47-A): GGCCACATCTCCGCGCCCGC SEQ ID NO: 3 (CD47-C): CCGCCGCCGCCGCAGGTGTCC SEQ ID NO: 4: (CD47-D): GGGCCACATCTCCGCGCCCGCCGC SEQ ID NO: 5: (CD47-E) CCGCCGTTACAGGCAGGACCGACC SEQ ID NO: 16 (CD47-A’): GGCCACATCTCCGCGCCCGCC [0190] Splice blocking morpholinos SEQ ID NO: 2, CD47-B (CD47-202_e1i1): AGCGAGGAGCCACTCACCGCAGCAC SEQ ID NO: 6, SB1 (CD47-202_e1i1’): GCGAGGAGCCACTCACCGCAGCAC SEQ ID NO: 7, SB2 (CD47-202_i1e2): CTGAGCTGATCCTGGAAAGGAAAAA SEQ ID NO: 8, SB3 (CD47-202_e2i2): TTCATAGAAGTCTTACCAACACGAT SEQ ID NO: 9, SB4 (CD47-202_e4i4): GAACTGCACATCTTACCTGGGACGA SEQ ID NO: 10, SB5 (CD47-202_e5i5): ACTGTAACAATGAAAACTCACCTGT SEQ ID NO: 11, SB6 (CD47-202_i5e6): CCAATCGCTGGAGGAAGGAAAAGGA SEQ ID NO: 12, SB7 (CD47-202_e6i6): TACAGAAAGATGACTCTTACCCGCA Filed October 18, 2024 SEQ ID NO: 13, SB8 (CD47-202_e8i8): TAAACTTTAACTTACCCTAGGAGGT SEQ ID NO: 14, SB9 (CD47-202_i9e10): GCTAGGATTAGTAACAAGCCAAGCA SEQ ID NO: 15, SB10 (CD47-202_e10i10): AGTGCATTTTATACTTACCATCATT [0191] In the following CD47 target sequences, brackets are shown (on sense strand) around the pre-mRNA target, to illustrate its position in the sequence; the start codon is indicated in parentheses. The target sequence of CD47-A (SEQ ID NOs: 1 / 16) is: GCGGCGGCGGCTGCTGCTCCGGACACCTGCGGCGGCGGCGGCGACCCCGC[GGCGGGC GCGGAG(ATG)TGGCC]CCTGGTAGCGGCGCTGT (SEQ ID NO: 69). The target sequence of CD47-B (SEQ ID NOs: 2 / 6) target sequence; splice blocker): CTCGGC[GTGCTGCGgtgagtggctcctcgct]cccagccc (SEQ ID NO: 70). The target sequence of CD47-C (SEQ ID NO: 3) is: GCGGCGGCGGCTGCTGCTCC[GGACACCTGCGGCGGCGGCGG]CGACCCCGCGGCGGG CGCGGAG(ATG)TGGCCCCTGGTAGCGGCGCTGT (SEQ ID NO: 71). The target sequence of CD47-D (SEQ ID NO: 4) is: GCGGCGGCGGCTGCTGCTCCGGACACCTGCGGCGGCGGCGGCGACCCC[GCGGCGGGC GCGGAG(ATG)TGGCCC]CTGGTAGCGGCGCTGT (SEQ ID NO: 72). Methods of Making Morpholino Oligonucleotides [0192] Methods of making morpholino oligonucleotides are known in the art (Summerton et al., Antisense and Nucleic Acid Drug Development, 7(3):187-195, 1997; Harakawa et al., Bioorganic & Medicinal Chemistry Letters, 22(3):1445-1447, 2012; Bhadra et al., Curr Prot Nucleic Acid Chem, 62: 4.65.1-4.65.26, 2015). Morpholino oligonucleotides also can be ordered commercially, for instance from a company such as Gene Tools LLC (Philomath, OR) and Gene Link Inc. (Hawthorne, NY). cGMP clinical grade morpholinos can be obtained from companies such as Anjinomoto Co. (Tokyo, Japan). See, for instance, U.S. Patent Nos. 5,506,337; 5,034,506; 5,142,047; 5,166,315; 5,185,444; 5,217,866; 5,235,033; 5,489,677; 5,521,063; 5,602,240; 5,698,685; 8,076,476; 8,299,206; 10,415,036; 11,230,565; and 11,434,486. Cell-Penetrating Peptide, and Attachment to Morpholino Oligonucleotide [0193] Cell-penetrating peptide (CPP) conjugates (a.k.a., peptide-oligomer conjugates) can be important for improving the therapeutic efficacy of morpholino oligonucleotides, for instance where the morpholinos have poor cellular uptake. Effective CPPs are considered to have the ability to deliver the morpholino oligonucleotides efficiently to the cell cytoplasm and nucleus, with minimal cell cytotoxicity. Cell-penetrating peptides useful for delivering oligonucleotides are known in the art. Examples include: L- and D-forms of R8, BPEP, Bac7, TAT, TATp, Penetratin, Hel11-7, DPV6, DPV7, MPG (Schissel et al., ACS Bio Med Chem Au, 2(2): 150-160, 2022); Filed October 18, 2024 sequences with RXR, RX, and RB repeats and sequences with D-arginine (Wu et al. Nucleic Acids Res, 35(15):5182-5191, 2007); and R6Pen (Lebleu et al., Adv Drug Deliv Rev, Mar 1;60(4- 5):517-29, 2008). See also: Reissmann, J Peptide Sci.20(10):760-784, 2014; Herce & Garcia, J Biol Phys 33(5-6):345-356, 2007; Derakhshankhah & Jafari, Biomed & Pharmacother., 108:1090- 1096, 2018; Xie et al., Front. Pharmacol.11, 2020; Szabó et al., Pharmaceutics 14(5):907, 2022. [0194] Thus, also provided are CD47-targeted morpholinos that are each conjugated to a cell- penetrating peptide (CPP). Conjugation of a CPP to a PMO is generally through an amide linker. CPP-conjugated morpholinos (PPMOs) are exemplified herein with three different CPPs: DG9 YArVRRrGPRGYArVRRrGPRrB (SEQ ID NO: 18; r = D-arginine, B = beta-alanine) (as described in Aslesh T et al., JCI Insight.2023 Mar 8;8(5): e160516); R6G: RRRRRRG (SEQ ID NO: 19; EP2170363B1); and r6G: rrrrrrG (SEQ ID NO: 20; r = D-arginine; EP2170363B1). However, other CPPs could be used with the herein described human-only CD47-targeted morpholino oligonucleotides. [0195] Table 2: Representative CPP-Conjugated CD47-Targeted Morpholino Oligomers : n O_N^o_i^{t D}_I C A

Filed October 18, 2024 : n O_N^o_i^t_a^D_I :_s

Filed October 18, 2024 [0196] Although exemplified herein with a CPP conjugated (that is, covalently bonded) at the 3’ end of the antisense morpholino sequence, also contemplated are hybrid molecules in which the CPP is attached at another position in the morpholino. By way of example, the CPP may be attached at the 5’ end of the morpholino oligonucleotide, or at any other position within the length of the morpholino. Placement of the CPP can be governed, for instance, by electing the oligonucleotide that is modified to accept addition of the CPP during synthesis via an amide linker. [0197] Optionally, a linker and/or a spacer may be included between the CPP and the CD47- targeted antisense morpholino oligonucleotide. Those of skill in the art will recognize spacers/linkers that may be useful. XI. Selection of Subjects for Treatment [0198] Subjects who will need reduction of CD47 expression and/or protection for non-cancer cells, tissues, and organs from radiation and/or chemotherapy damage while increasing cancer killing will be selected for treatment. [0199] Subjects exposed to radiation or chemotherapy as part of their occupation, by accident, non-cancer related use of radiation or chemotherapy for any treatment, or in military settings will be candidates for treatment. [0200] The provided CD47 morpholinos are applicable for treatment of individuals with solid and liquid cancers, who will receive chemotherapy and or radiation and or check point blockers and or engineered CART cells as part of their treatment plan. They are also applicable to individuals exposed to radiation or chemotherapy for reasons unrelated to cancer therapy. XII. Administration of Human-Specific CD47 Morpholino Oligonucleotides [0201] An effective amount of a compound (such as a morpholino oligonucleotide, or a morpholino oligonucleotide conjugated to a cell penetrating peptide) may be administered in a single dose, or in several doses, for example daily, or periodically with intervals of no treatment of several days or longer, during a course of treatment. However, the effective amount will be dependent on the compound applied, the subject being treated, the severity and type of the affliction, and the manner of administration of the compound. For example, a therapeutically effective amount of an active ingredient can be measured as the concentration (moles per liter or molar-M) of the active ingredient (such as a nucleic acid molecule, peptide, or fusion between a nucleic acid molecule and peptide) in blood (in vivo) or a buffer (in vitro) that produces an effect. [0202] Therapeutically effective dosages of published morpholinos are generally in the range of 1-10 μM. However, data herein demonstrate that the human-only CD47 morpholinos show effective lowering of CD47 protein and cell responses in the lower range of concentrations and even ≤1 µM, a degree of effectiveness not found with other published, known, or reported morpholinos. Filed October 18, 2024 [0203] Specifically contemplated herein are treatments that employ more than one of the described morpholinos, administered either concurrently (in the same composition or different compositions) or in series. Combinations of at least one translation blocking morpholino and at least one splice blocking morpholino are specifically contemplated. By way of example, administration of both CD47-A and CD47-B morpholinos, for instance each with an attached CPP, is provided in some embodiments. In combination morpholino embodiments, the conjugated CPP may be the same on the different morpholinos; in other examples, the CPP conjugated to each type of morpholino is different. [0204] Specifically contemplated herein are treatments that employ more than one of the described morpholinos, administered in a carrier such an endosome (Evans et al., Nat Commun. 10(1):501, 2019). This formulation achieved increased cytosolic delivery of a CD47 morpholino in human cells. The same is contemplated for exosomes and other nano-packaging technologies. [0205] In applications for cancer therapy, the CD47 morpholino will be given as an intravenous infusion to permit the widest cell and tissue access for the agent. For other indications, more regional targeting of agent delivery may be appropriate. [0206] The CD47 morpholinos can be given prior to, or at the same time as a genotoxic stress for cancer via intravenous injection or other methods. This latter feature is unexpected and unprecedented based on prior studies and reports of CD47 morpholinos. Prior knowledge taught that CD47 morpholinos had to be given several days prior to the genotoxic stress to obtain protein suppression and therapeutic benefit. Data herein provided indicate that the provided human-only CD47 morpholinos have therapeutic effects prior to demonstrable lowering of total CD47 protein. [0207] The therapeutic compounds described herein may be formulated in a variety of ways depending on the location and type of disease to be treated or prevented in the subject. Pharmaceutical compositions are thus provided for both local use at or near an affected area and for systemic use (in which the agent is administered in a manner that is widely disseminated via the cardiovascular and lymphatic systems). [0208] Pharmaceutical compositions that include at least one morpholino oligonucleotide, optionally fused with a peptide (e.g., a CPP) described herein as an active ingredient, or that include both a therapeutic morpholino oligonucleotide and an additional agent as active ingredients, or that include both a radioprotective peptide or inhibitor and an additional therapeutic agent, may be formulated with an appropriate solid or liquid carrier, depending upon the particular mode of administration chosen. [0209] A suitable administration format may best be determined by a medical practitioner for each subject individually. Various pharmaceutically acceptable carriers and their formulation are described in standard formulation treatises, for example, Remington's Pharmaceutical Sciences by E. W. Martin. See also Wang and Hanson, J. Parenteral Sci. Technol., Technical Report No.10, Supp.42: 2S, 1988. Filed October 18, 2024 [0210] The dosage form of the pharmaceutical composition will be determined by the mode of administration chosen. For instance, in addition to injectable fluids, inhalational, topical, ophthalmic, peritoneal, intra-pleural, trans-cranial, intra-cerebrospinal, intravenous, and oral formulations can be employed. Inhalational preparations can include aerosols, mists, nebulizers, particulates, and the like. In general, the goal for particle size for inhalation is 1 μm or less in order that the pharmaceutical reach the alveolar region of the lung for absorption. Oral formulations may be liquid (for example, syrups, solutions, or suspensions), or solid (for example, powders, pills, tablets, lozenges, or capsules). For solid compositions, conventional non-toxic solid carriers can include pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. Actual methods of preparing such dosage forms are known, or will be apparent, to those of ordinary skill in the art. [0211] The compositions or pharmaceutical compositions can be administered by any route including parenteral administration, for example, intravenous, intramuscular, intraperitoneal, intra-sternal, or intra-articular injection or infusion, or by intra-bone marrow space injection such as via the anterior tibia, or by sublingual, oral, topical, intra-nasal, ophthalmic, or transmucosal administration, or by pulmonary inhalation. When the active compounds are provided as parenteral compositions, for example, for injection or infusion, they are generally suspended in an aqueous carrier, for example, in an isotonic buffer solution at a pH of 3.0 to 8.0, preferably at a pH of 3.5 to 7.4, 3.5 to 6.0, or 3.5 to 5.0. Useful buffers include sodium citrate-citric acid and sodium phosphate-phosphoric acid, and sodium acetate/acetic acid buffers. A form of repository or depot slow-release preparation may be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following transdermal injection or delivery. The agent may also be part of (e.g., coated on surface(s) of) an implantable device such as a stent, vascular conduit, catheter, pump, or other engineered implant or scaffold, the latter sometimes seeded with cells of various types, from which it will be released. [0212] Active compounds (e.g., oligonucleotides, peptides, and fusions thereof) are also suitably administered by sustained-release systems. Suitable examples of sustained-release formulations include suitable polymeric materials (such as, for example, semi-permeable polymer matrices in the form of shaped articles, for example, films, or microcapsules), suitable hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, and sparingly soluble derivatives (such as, for example, a sparingly soluble salt). Sustained- release compounds may be administered by intravascular, intravenous, intra-arterial, intramuscular, subcutaneous, intra-pericardial, or intra-coronary injection. Administration can also be oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (as by powders, ointments, gels, drops or transdermal patch), buccal, or as an oral or nasal spray. [0213] Preparations for administration can be suitably formulated to give controlled release of the therapeutic agent(s) (e.g., oligonucleotides or oligonucleotide/peptide fusions). For example, the Filed October 18, 2024 pharmaceutical compositions may be in the form of particles comprising a biodegradable polymer and/or a polysaccharide jellifying and/or bio-adhesive polymer, an amphiphilic polymer, an agent modifying the interface properties of the particles and a pharmacologically active substance. These compositions exhibit certain biocompatibility features that allow a controlled release of the active substance. See, for example, U.S. Pat. No.5,700,486. [0214] In some embodiments, therapeutic agent(s) are delivered by way of a pump (see Sefton, CRC Crit. Ref. Biomed. Eng.14:201, 1987; Buchwald et al., Surgery 88:507, 1980; Saudek et al., N. Engl. J. Med.321:574, 1989) or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution may also be employed. The key factor in selecting an appropriate dose is the result obtained, as measured by increases or decreases in radioprotection or protection from chemotherapy-mediated injury, or by other criteria for measuring control or prevention of disease, as are deemed appropriate by the practitioner. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533, 1990). [0215] In another aspect of the disclosure, therapeutic agent(s) are delivered by way of an implanted pump, described, for example, in U.S. Pat. No. 6,436,091; U.S. Pat. No. 5,939,380; and U.S. Pat. No.5,993,414. Implantable drug infusion devices are used to provide subjects with a constant and long-term dosage or infusion of a drug or any other therapeutic agent. Essentially, such device may be categorized as either active or passive. [0216] Active drug or programmable infusion devices feature a pump or a metering system to deliver the drug into the individual’s system. An example of such an active drug infusion device currently available is the Medtronic SynchroMed™ programmable pump. Such pumps typically include a drug reservoir, a peristaltic pump to pump the drug out from the reservoir, and a catheter port to transport the pumped-out drug from the reservoir via the pump to an individual’s anatomy. Such devices also typically include a battery to power the pump, as well as an electronic module to control the flow rate of the pump. The Medtronic SynchroMed™ pump further includes an antenna to permit the remote programming of the pump. [0217] An implanted pump can be completely implanted under the skin of a subject, thereby negating the need for a percutaneous catheter. These implanted pumps can provide the individual with therapeutic agent(s) at a constant or a programmed delivery rate. Constant rate or programmable rate pumps are based on either phase-change or peristaltic technology. When a constant, unchanging delivery rate is required, a constant-rate pump is well suited for long-term implanted drug delivery. If changes to the infusion rate are expected, a programmable pump may be used in place of the constant rate pump system. Osmotic pumps may be much smaller than other constant rate or programmable pumps, because their infusion rate can be very low. An example of such a pump is described listed in U.S. Pat. No.5,728,396. Filed October 18, 2024 [0218] Passive drug infusion devices, in contrast, do not feature a pump, but rather rely upon a pressurized drug reservoir to deliver the drug. Thus, such devices tend to be both smaller as well as cheaper as compared to active devices. An example of such a device includes the Medtronic IsoMed™. This device delivers the drug into the patient through the force provided by a pressurized reservoir applied across a flow control unit. [0219] The therapeutic agents may also be delivered passively and in sustained fashion as part of and incorporated into implantable devices, such as vascular stents which can be placed directly into diseased blood vessels through several standard approaches, including direct surgical insertion or percutaneously with angiographic control. Other formations may be combined with osteo-integrated implants to promote bone healing. [0220] The CD47 morpholinos are quite water soluble and stable and thus ensure that their use with implantable and other delivery technology will provide a therapeutically active agent. [0221] For oral administration, the pharmaceutical compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (for example, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or sodium starch glycolate); or wetting agents (for example, sodium lauryl sulphate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example, methyl or propyl-p- hydroxybenzoates or sorbic acid). The preparations can also contain buffer salts, flavoring, coloring, and sweetening agents as appropriate. The herein provided CD47 morpholinos are stable and will and do not react with any of the agents listed above. [0222] For administration by inhalation, the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Filed October 18, 2024 [0223] For topical administration, the compounds can be, for example, mixed with a liquid delivery agent for administration locally. The agents used therapeutically (such as peptides, antibodies and morpholinos) are readily soluble or can be suspended in water and saline, and as such these would be useful for delivery since water or saline do not cause adverse biological tissue effects. This allows sufficiently high doses to be administered locally or systemically, without secondary toxicity from the delivery vehicle. In this same line, the morpholinos could be part of a patch placed on the skin (that is, a transdermal delivery patch) that would deliver the agent to the skin for absorption. [0224] Pharmaceutical compositions that comprise at least one therapeutic agent as described herein as an active ingredient will normally be formulated with an appropriate solid or liquid carrier, depending upon the particular mode of administration chosen. The pharmaceutically acceptable carriers and excipients useful in this disclosure are conventional. For instance, parenteral formulations usually comprise injectable fluids that are pharmaceutically and physiologically acceptable fluid vehicles such as water, physiological saline, other balanced salt solutions, aqueous dextrose, glycerol or the like. Excipients that can be included are, for instance, proteins, such as human serum albumin or plasma preparations. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art. [0225] For example, for parenteral administration, therapeutic agent(s) can be formulated generally by mixing them at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, for instance, one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. A pharmaceutically acceptable carrier is a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. [0226] Generally, the formulations are prepared by contacting the therapeutic agent(s) each uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Optionally, the carrier is a parenteral carrier, and in some embodiments, it is a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes. The agent could also be included within a transfused human product such a blood, plasma, platelets, bone marrow cells, etc. [0227] The pharmaceutical compositions that comprise at least one therapeutic agent, in some embodiments, will be formulated in unit dosage form, suitable for individual administration of precise dosages. The amount of the active compound(s) administered will be dependent on the Filed October 18, 2024 subject being treated, the severity of the affliction, and the manner of administration, and is best left to the judgment of the prescribing clinician. Within these bounds, the formulation to be administered will contain a quantity of the active component(s) in amounts effective to achieve the desired effect in the subject being treated. [0228] The therapeutically effective amount of the agent, such as an oligonucleotide (e.g., morpholino or other antisense molecule) will be dependent on the agent utilized, the subject being treated, the severity and type of the affliction, and the manner of administration. The exact dose is readily determined by one of skilled in the art based on the potency of the specific compound, the age, weight, sex, and physiological condition of the subject. [0229] The therapeutic agents can also be administered directly as part of a surgical or other medical procedure, or at the bedside by a treating physician. Drug quality product (e.g., morpholino) can be diluted for instance in sterile saline and given by injection using sterile 1 cc syringes and small-bore needles (25 gauge and less) to a subject in need of radioprotection. Alternatively, a wound bed can be irrigated for instance with a saline or other therapeutically effective solution containing a known concentration (dosage) of drug or compound, or a combination thereof. Precise control and localization of therapeutic effects can thus be obtained. [0230] The agent may also be instilled into a transplanted organ prior to transplantation, such as a kidney, liver, heart, or lungs via the vasculature to minimize organ injury and enhance organ take, survival, and function after transplantation. [0231] Controlled release parenteral formulations can be made as implants, oily injections, or as particulate systems. For a broad overview of protein delivery systems, see Banga, Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems, Technomic Publishing Company, Inc., Lancaster, Pa., 1995. Particulate systems include microspheres, microparticles, microcapsules, nano-capsules, nanospheres, and nanoparticles. Microcapsules contain the therapeutic peptide as a central core. In microspheres, the therapeutic agent is dispersed throughout the particle. Particles, microspheres, and microcapsules smaller than 1 μm are generally referred to as nanoparticles, nanospheres, and nano-capsules, respectively. Capillaries have a diameter of approximately 5 μm so that only nanoparticles are administered intravenously. Microparticles are typically around 100 μm in diameter and are administered subcutaneously or intramuscularly (see Kreuter, Colloidal Drug Delivery Systems, J. Kreuter, ed., Marcel Dekker, Inc., New York, N.Y., pp.219-342, 1994; Tice & Tabibi, Treatise on Controlled Drug Delivery, A. Kydonieus, ed., Marcel Dekker, Inc. New York, N.Y., pp.315-339, 1992). CD47 morpholino can also be delivered efficiently to cells via endosomes (Evans et al., Nat Commun.10(1):501, 2019). [0232] Also contemplated is the use of nanoparticles as delivery agents, which can be targeted to specific cells, tissues or organ for instance by incorporation on their surface ligands of receptors specific in their expression to the targeted cells, tissues or organs. The targeting entity can be the same or different than the therapeutically active agent carried by the nanoparticle. Filed October 18, 2024 Further, distribution of nanoparticles to certain tissues spaces (e.g. the blood versus the central nervous system protected by the blood-brain barrier) can be determined by altering the size of the nanoparticles thereby allowing or preventing their transit of such barriers between tissue compartments and through displaying target-cell specific antigen(s) on the surface of the nanoparticles to yield precision directed therapy. The same applies to delivery methods above. [0233] Polymers can be used for ion-controlled release. Various degradable and nondegradable polymeric matrices for use in controlled drug delivery are known in the art (Langer, Accounts Chem. Res.26:537, 1993). For example, the block copolymer, poloxamer 407 exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature. It has shown to be an effective vehicle for formulation and sustained delivery of recombinant interleukin-2 and urease (Johnston et al., Pharm. Res.9:425, 1992; Pec, J. Parent. Sci. Tech.44(2):58, 1990). Alternatively, hydroxyapatite has been used as a microcarrier for controlled release of proteins (Ijntema et al., Int. J. Pharm.112:215, 1994). In yet another aspect, liposomes are used for controlled release as well as drug targeting of lipid-capsulated compounds (Betageri et al., Liposome Drug Delivery Systems, Technomic Publishing Co., Inc., Lancaster, Pa., 1993). Numerous additional systems for controlled delivery of therapeutic proteins are known (e.g., U.S. Pat. No.5,055,303; U.S. Pat. No.5,188,837; U.S. Pat. No.4,235,871; U.S. Pat. No.4,501,728; U.S. Pat. No.4,837,028; U.S. Pat. No. 4,957,735; and U.S. Pat. No.5,019,369; U.S. Pat. No. 5,055,303; U.S. Pat. No.5,514,670; U.S. Pat. No.5,413,797; U.S. Pat. No.5,268,164; U.S. Pat. No.5,004,697; U.S. Pat. No.4,902,505; U.S. Pat. No.5,506,206; U.S. Pat. No.5,271,961; U.S. Pat. No.5,254,342; and U.S. Pat. No.5,534,496). Such polymers may take the form of mesh and matrix or similar supporting type materials used for enhanced wound healing and tissue healing. [0234] The specific form of the agents and their manner of administration may also be influenced, at least in part, by the particular tissue to be treated. [0235] The amount of agent to be delivered, as well as the dosing schedule useful to provide the desired protective effects, will be influenced by the bioavailability of the specific therapeutic compound selected (and/or an active metabolite thereof), the type and extent of radiation exposure or radiation dosage schedule, and other factors that will be apparent to those of skill in the art. [0236] Alternatively, the compound may be administered in a gel, lotion, ointment, or other suitable form which is applied to the tissue up to 90 minutes before irradiation or treatment and remains on the tissue during and optionally after the treatment. [0237] The same dosage and concentrations can be used when the radioprotective agent is administered after irradiation and/or radiotherapeutic treatment. The three administrations (before, during and after radiotherapy treatment) may be used alone, or in any combination of two or all three administrations, as needed. Filed October 18, 2024 [0238] The provided human-only CD47 morpholinos described herein are the first ever to be effective against genotoxic stress when administered at the same time as the stress. XIII. Determination of Effectiveness of Treatment [0239] Therapeutic effect following morpholino administration may be followed and tracked through analysis of CD47 protein expression, both total and cell surface (Bmax), in circulating blood cells or cells from other body fluids such as cerebrospinal or pleural fluids. Peripheral blood mononuclear cells will be isolated from blood samples and protein expression characterized by flow cytometry, a method we have standardized, and / or Western blot as shown herein. [0240] Lowering of total and or cell surface CD47 expression on cells from the blood and other body fluids would be taken as evidence of CD47 morpholino activity and will show correlation with therapeutic effect. In instances where tumor tissue are available from individuals given the CD47 morpholino, samples could be assessed via several technique for CD47 expression including immunohistochemistry, immunofluorescence, flow cytometry, or Western blot as published (Erdem et al., Am J Physiol Endocrinol Metab.2023 Apr 1;324(4): E347-E357). XIV. Co-Administration of Additional Therapeutic Compound(s) [0241] Data indicate that the CD47 morpholinos lower CD47 protein to maximum effect 24-72 hours after administration. However, in combination with genotoxic stress it also enhanced non- cancer cell viability when given at the same time as the stressor (e.g., chemotherapy). Thus, the morpholino will be administered either at the same time as or 1-3 days prior to chemotherapy or radiation or other cancer agents. [0242] Additional active ingredients include, for example, nitric oxide donors, nitro-vasodilators, activators of the enzyme soluble guanylyl cyclase, or cGMP phosphodiesterase inhibitors. Pharmaceutical compositions may include additional cytoprotective or radioprotective agents known to the art (for example as described in Tofilon, Chem. Rev.109:2974-88, 2009). [0243] The Exemplary Embodiments and Experimental Examples below are included to demonstrate particular embodiments of the disclosure. Those of ordinary skill in the art should recognize in light of the present disclosure that many changes can be made to the specific embodiments disclosed herein and still obtain a like or similar result without departing from the spirit and scope of the disclosure. XV. Exemplary Embodiments [0244] 1. A CD47 antisense morpholino oligonucleotide including a nucleic acid sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 (CD47-A’), SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, Filed October 18, 2024 SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47- 202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10). [0245] 2. A CD47 antisense morpholino oligonucleotide including a nucleic acid with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 (CD47-A’), SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47- 202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10). [0246] 3. The CD47 antisense morpholino oligonucleotide of embodiment 1 or embodiment 2, further including a cell-penetrating peptide (CPP) conjugated to the oligonucleotide. [0247] 4. The CD47 antisense morpholino oligonucleotide of embodiment 3, wherein the CPP is conjugated at the 5’ end of the oligonucleotide. [0248] 5. The CD47 antisense morpholino oligonucleotide of embodiment 3, including a sequence as shown in any one of SEQ ID NOs: 21-68. [0249] 6. A non-naturally occurring antisense oligonucleotide specific for human CD47, the sequence of which consists essentially of the sequence set forth in any of: SEQ ID NO: 1 (CD47- A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 (CD47-A’), SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47- 202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10). [0250] 7. The non-naturally occurring antisense oligonucleotide of embodiment 6, which includes at least one morpholino ring. [0251] 8. The non-naturally occurring antisense oligonucleotide of embodiment 6 or embodiment 7, further including a cell-penetrating peptide (CPP) conjugated to the oligonucleotide. [0252] 9. The non-naturally occurring antisense oligonucleotide of embodiment 8, wherein the CPP is conjugated at the 5’ end of the oligonucleotide. [0253] 10. The non-naturally occurring antisense oligonucleotide of embodiment 8, including a sequence as shown in any one of SEQ ID NOs: 21-68. [0254] 11. A hybrid nucleic acid-peptide fusion molecule including: an antisense oligonucleotide specific for human CD47, and including a nucleic acid sequence set forth in any Filed October 18, 2024 of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 (CD47-A’), SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47- 202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47- 202_e10i10); and a peptide covalently attached to the antisense oligonucleotide. [0255] 12. The fusion molecule of embodiment 11, wherein the peptide is covalently attached at the 5’ end of the antisense oligonucleotide. [0256] 13. The fusion molecule of embodiment 11, wherein the peptide includes a cell penetrating peptide (CPP) or other cell targeting sequence. [0257] 14. The fusion molecule of embodiment 13, wherein the peptide includes: DG9 YArVRRrGPRGYArVRRrGPRrB (SEQ ID NO: 18; r = D-arginine, B = beta-alanine); R6G: RRRRRRG (SEQ ID NO: 19); or r6G: rrrrrrG (SEQ ID NO: 20; r = D-arginine). [0258] 15. The fusion molecule of embodiment 13, including a sequence as shown in any one of SEQ ID NOs: 21-68. [0259] 16. A composition including: at least one therapeutic molecule selected from: the CD47 antisense morpholino oligonucleotide of any one of embodiments 1-5; the non-naturally occurring antisense oligonucleotide of any one of embodiments 6-10; or the hybrid nucleic acid- peptide fusion molecule of any one of embodiments 11-15; and at least one biologically or pharmaceutically acceptable excipient or carrier. [0260] 17. The composition of embodiment 16, formulated for delivery to a subject. [0261] 18. The formulated composition of embodiment 17, formulated to be delivered to the subject transdermally, intramuscularly, intravascularly, by inhalation, or intranasally. [0262] 19. The composition of embodiment 16, including at least two of the therapeutic molecules. [0263] 20. The composition of embodiment 19, wherein the at least two therapeutic molecules include: at least one oligonucleotide with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), or SEQ ID NO: 16 (CD47-A’); and at least one oligonucleotide with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 2, CD47-B (CD47- 202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47- 202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10). Filed October 18, 2024 [0264] 21. A composition including a plurality of different CD47 antisense morpholino oligonucleotides of any of embodiments 1-5. [0265] 22. A composition including a plurality of different non-naturally occurring antisense oligonucleotides of any one of embodiments 6-10. [0266] 23. A composition including a plurality of different hybrid nucleic acid-peptide fusion molecules of any one of embodiments 11-15. [0267] 24. The composition of any one of embodiments 20-23, wherein the at least two oligonucleotides or fusion molecules include: at least one oligonucleotide with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47- C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), or SEQ ID NO: 16 (CD47-A’); and at least one oligonucleotide with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47- 202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10). [0268] 26. The CD47 antisense morpholino oligonucleotide of any one of embodiments 1-5, the non-naturally occurring antisense oligonucleotide of any one of embodiments 6-10, the hybrid nucleic acid-peptide fusion molecule of any one of embodiments 11-15, or the composition of any one of embodiments 16-24, for use in modulating CD47 signalling in a subject. [0269] 27. The CD47 antisense morpholino oligonucleotide of any one of embodiments 1-5, the non-naturally occurring antisense oligonucleotide of any one of embodiments 6-10, the hybrid nucleic acid-peptide fusion molecule of any one of embodiments 11-15, or the composition of any one of embodiments 16-24, for use in a method of reducing cytotoxicity or genotoxicity of an agent in a subject. [0270] 28. A method including administering to a subject a CD47-level reducing amount of an agent selected from: the CD47 antisense morpholino oligonucleotide of any one of embodiments 1-5, the non-naturally occurring antisense oligonucleotide of any one of embodiments 6-10, the hybrid nucleic acid-peptide fusion molecule of any one of embodiments 11-15, or the composition of any one of embodiments 16-24. [0271] 29. The method of embodiment 28, which reduces at least one cytotoxic or at least one genotoxic effect of an agent in the subject. [0272] 30. The method of embodiment 28, wherein the agent includes a chemotherapeutic agent, a radionuclide administered as part of a radiation treatment or other radiation exposure, or another cytotoxic or genotoxic agent administered to the subject. [0273] 31. The method of embodiments 28-30, wherein the agent is administered transdermally, intramuscularly, intravascularly, by inhalation, or intranasally. Filed October 18, 2024 [0274] 32. A method of reducing cytotoxicity of a chemotherapeutic agent to non-cancer cells in a subject with cancer, including: administering to the subject an effective amount of a CD47 antisense morpholino oligonucleotide including the nucleic acid sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47- E), SEQ ID NO: 16 (CD47-A’), SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47- 202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47- 202_e10i10); and one or more chemotherapeutic agents, [0275] wherein the CD47 antisense morpholino inhibits CD47 signaling and is administered to the subject before, during, or after administration of the one or more chemotherapeutic agents. [0276] 33. The method of embodiment 32, wherein the antisense morpholino oligonucleotide further includes a cell-penetrating peptide (CPP) conjugated to the oligonucleotide. [0277] 34. The method of embodiment 33, wherein the CPP is conjugated at the 5’ end of the oligonucleotide. [0278] 35. The method of embodiment 33, antisense morpholino oligonucleotide includes a sequence as shown in any one of SEQ ID NOs: 21-68. [0279] 36. The method of embodiments 32-35, in which the antisense morpholino oligonucleotide is administered transdermally, intramuscularly, intravascularly, by inhalation, or intranasally. [0280] 37. A method of reducing cytotoxicity of a chemotherapeutic agent to non-cancer cells, including: (a) administering an effective amount of at least one CD47 morpholino oligonucleotide including the nucleic acid sequence set forth as in any of: SEQ ID NO: 1 (CD47- A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 (CD47-A’), SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47- 202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10) to a subject with cancer; (b) administering one or more chemotherapeutic agents to the subject with cancer, wherein (a) and (b) can be performed in either order or concurrently; and (c) detecting a reduction of cytotoxicity to non-cancer cells in the subject. [0281] 38. The method of embodiment 37, wherein the antisense morpholino oligonucleotide further includes a cell-penetrating peptide (CPP) conjugated to the oligonucleotide. [0282] 39. The method of embodiment 38, wherein the CPP is conjugated at the 5’ end of the oligonucleotide. Filed October 18, 2024 [0283] 40. The method of embodiment 38, antisense morpholino oligonucleotide includes a sequence as shown in any one of SEQ ID NOs: 21-68. [0284] 41. The method of embodiments 37-40, wherein the antisense morpholino oligonucleotide is administered transdermally, intramuscularly, intravascularly, by inhalation, or intranasally. [0285] 42. The method of any one of embodiments 35-38, wherein the oligonucleotide agent is delivered concurrently with the cytotoxic or genotoxic challenge. [0286] 43. The method of any one of embodiments 28-42, including administering at least one splice blocker oligonucleotide and at least one translation blocker oligonucleotide. [0287] 44. The method of embodiment 43, wherein: the at least one splice blocker oligonucleotide has a sequence consisting of the sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), or SEQ ID NO: 16 (CD47-A’); and the at least one translation blocker oligonucleotide has a sequence consisting of the sequence set forth in any of: SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47- 202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47- 202_e10i10). [0288] 45. The method of embodiment 43 or embodiment 44, wherein the splice blocker oligonucleotide and/or the translation blocker oligonucleotide further includes a cell penetrating peptide (CPP) conjugated thereto. [0289] 46. The method of embodiment 45, wherein the splice blocker oligonucleotide and/or the translation blocker oligonucleotide is selected from SEQ ID NOs: 21-68. [0290] 47. The method of any one of embodiments 28-46, wherein the subject is a human. [0291] 48. The method of embodiment 47, wherein the subject is immunocompromised. [0292] 49. The method of embodiment 47, wherein the therapeutic agent(s) is administered transdermally, intramuscularly, intravascularly, by inhalation, or intranasally. XVI. Experimental Examples Example 1: Testing cell uptake-enhanced CD47 morpholinos for cytotoxicity, effectivity of decreasing CD47 protein levels in cells, and decreasing sensitivity of cells to chemotherapy. [0293] CD47 morpholinos conjugated to uptake-enhanced cell-penetrating peptide were tested for cytotoxicity, ability to decrease CD47 protein expression, both total and cell surface, and ability to reduce sensitivity of cells to the standard cytotoxic chemotherapeutic agent Doxorubicin. Cell uptake-enhanced CD47 morpholinos were non-toxic to several types of primary human cells from Filed October 18, 2024 different distinct cell lineages. Of note, all CD47 morpholinos previously described in the literature were employed as naked entities lacking any modifications to enhance cell uptake. This was true for studies that treated cells in vitro or that treated animals with the morpholino. Yet, to be effective in human disease, morpholinos are modified to increase their delivery and increase uptake by cells. It was not known if a CD47 morpholino conjugated to a cell uptake-enhancing peptide would be inherently cytotoxic. This was an important question to test as such a construct could have been injurious. [0294] It was established that such uptake-enhanced cell-penetrating peptide conjugated CD47 morpholinos were not cytotoxic at concentrations that showed lowering of CD47 protein expression and increased viability and protection from the chemotherapy agent in primary human cells. The highest morpholino concentrations were substantially greater than that which will be used in treating individuals (FIGs.7-11). These are important finding that pave the way forward for developing CD47 morpholino sequences conjugated to cell uptake-enhancing peptides. As well, different cell uptake-enhancing peptide conjugated to the CD47 morpholino were found to be nontoxic to human cells, indicating that multiple uptake-enhancing cell-penetrating peptides do not render the CD47 morpholinos inherently toxic. This finding provides flexibility in development of cell uptake strategies. Studies were repeated at least 3 times. Representative data is presented. [0295] A cell uptake-enhanced CD47 morpholino decreased CD47 protein levels in human cells in a dose-dependent manner. As it was published, the therapeutic benefit in any CD47 morpholino resides in its ability to lower CD47 protein. Thus, this remains the first initial step in confirming bio-activity of a CD47 morpholino. It was established that a cell uptake-enhancing peptide conjugated CD47 morpholino lowered total CD47 protein in multiple human primary cell types. The peptide modified morpholino showed dose-dependent activity in lowering CD47 protein in human immune T cells (FIGs. 15 and 16). This confirmed that the cell uptake enhancement to the CD47 morpholino did not interfere with the protein lowering capacity of the morpholino. This was important to check, as some data suggest the cell uptake enhancing peptides may be inflammatory (Lebleu et al., Adv Drug Deliv Rev.2008 Mar 1;60(4-5):517-29). This could have been an issue as CD47 and TSP1 are increased by inflammation. Indeed, by increasing cell uptake the peptide modification of the morpholino is actually predicted to improve the CD47 morpholino efficacy and permit lower dosing. Of note, a non-specific CD47 morpholino had no effect on CD47 protein expression levels. How human cells would respond to any CD47 morpholino conjugated to a cell-penetrating peptide was unknown. Following these studies, the other human-only CD47 morpholino oligonucleotides were tested. Studies were repeated at least 3 times. Representative data is presented. [0296] A cell uptake enhancement CD47 morpholino decreases sensitivity of primary non-cancer human cells to chemotherapy. The principal behind the CD47 morpholino is that it protects non- Filed October 18, 2024 cancer cells, tissues, organs, and animals from genotoxic injury from chemotherapy and radiation. In so doing, it preserves and enhances immune cell killing of cancers, and blocks the unwanted side effects and complications of chemotherapy and radiation on non-cancer cells. Human cells treated with the cell uptake-enhancing peptide CD47 morpholino showed cell growth in the presence of Doxorubicin, a widely used cancer chemotherapy agent (FIGs.29-33). Thus, lowering CD47 mitigated the killing activity of the chemotherapeutic agent on primary human non- cancer cells. Additionally, these data demonstrated that simultaneous administration of the cell- penetrating peptide conjugated CD47 morpholino and the chemotherapy Doxorubicin did not limit the protective effects of the morpholino. Prior to this discovery, it was believed that cells and animals required 48 to 72 hours of pre-treatment with a CD47 morpholino to obtain therapeutic protection from genotoxic stress (Isenberg et al., Circ Res.2007 Mar 16;100(5):712-20; Isenberg et al., Ann Surg. 2008 Jan;247(1):180-90; Isenberg et al., Ann Surg. 2008 May;247(5):860-8; Maxhimer et al., Sci Transl Med. 2009 Oct 21;1(3):3ra7). This enhanced activity of the human only CD47 morpholinos may be secondary to the human-only sequence targeting, actions of the cell-penetrating peptide, or a combination of these. In any case, this feature of the CD47 morpholinos provided herein will have a positive impact on the application of the therapies in the clinic. Example 2: Design of unique human-only targeting CD47 morpholinos. [0297] A portfolio of one-of-a-kind never before constructed translational and splice blocking morpholinos that specifically target the human CD47 gene only were designed (FIG.6). Example 3: Assays to determine CD47 protein expression in human cells. [0298] A flow cytometry assay was developed to determine CD47 compartment expression in human cells treated with a CD47 morpholino. Total (cytoplasmic and cell surface) CD47 expression was measured. This permits compartment-specific CD47 expression details to be acquired. As a cell surface receptor characterization of cell surface protein copy number (Bmax) is important to understanding the mechanism of action of the morpholinos. This approach has not been attempted or demonstrated previously. [0299] As a major cell regulator, CD47 resides on the surface of all cells and interacts with its primary high affinity soluble ligand TSP1 (Isenberg et al., J Biol Chem, 284(2):1116-1125, 2009) and in cis with other same cell membrane receptor ectodomains. Total CD47 protein levels reflect the combination of CD47 located in various compartment of cells including the cytoplasm, peri- nuclear area, ER, and the outer cell membrane. The cell surface protein is the active receptor. The effect of a CD47 morpholino on the several cell compartments of CD47, and especially cell Filed October 18, 2024 surface CD47, has not previously been tested. Thus, results provided herein showing that the new CD47 morpholinos lower cell surface receptor CD47 protein are of particular interest. [0300] Using flow cytometry and human cells, total CD47 expression (cytoplasmic and cell surface) changes in response to the cell-penetrating conjugated CD47 morpholinos, DG9-CD47- 1 (DG9-CD47-A) (SEQ ID NO: 21) and DG9-NC705 (SEQ ID NO: 73), was characterized (FIGs. 27, 28). CD47 protein levels decreased in CD47 morpholino treated cells at low concentration of 1-2 to 10 µM consistent with findings on Western blot (FIGs.15-24). Thus, both Western blot and flow cytometry confirmed that the cell-penetrating peptide conjugated CD47 morpholino lowered protein levels at quite low concentrations. Indeed, substantial lowering of protein (~50%) was found in some studies at ≤1 µM concentrations of the CD47 morpholino. This is a manifestation of greater sequence specificity and enhanced morpholino delivery across the cell membrane. [0301] These ongoing studies may provide new mechanistic insights into mechanism(s) or action of the human-only CD47 morpholinos. The assay may permit comparison of cell surface CD47 to total protein. The assay may also allow routine characterization of the relative copy number of CD47 molecules on cells (B_max) at baseline and under stress. And, these data may be obtained on cells in the immune compartment such as macrophages, and T, NK, and dendritic cells. In this location, as was shown by Isenberg and colleagues, CD47 may play a role as a determinate of self (Dai et al., Sci Immunol.2(12): eaam6202, 2017). It may be expected that immune cell CD47 expression will reflect and/or predict immune response to tumors following treatment with the CD47 morpholino. In this regard, these data may be used to inform design of clinical trials permitting flow cytometry analysis and or Western blot of PBMC levels of CD47 as a demonstration of target modulation and tissue changes in other areas. This applies to cells from other body fluids such as cerebrospinal fluid and would be relevant to individuals given a CD47 morpholino for glioblastoma. As well, flow cytometry may provide confirmatory protein expression validation of Western blot data. Further, the analysis of soluble to TSP1 in plasma and other body fluids will be tracked and can be done using ELISA as published (Erdem et al., Am J Physiol Endocrinol Metab. 324(4): E347-E357, 2023). These assays will be part of a simple and reproducible biomarker and therapeutic effect index kit. They will help to provide personalized insights in tumor biology relevant to and specific for treated individuals and the response to a CD47 morpholino. [0302] Studies were repeated at least 3 times. Representative data is presented. The flow cytometry assay may be used to demonstrate a possible checkpoint blocking function in cells based upon the CD47 morpholino lowering cell surface CD47 (FIGs.25-28). As well, the CD47 morpholinos are predicted to alter immune cells from treated individuals. This indicates another method of tracking CD47 morpholino effect, namely using immune cells from CD47 morpholino- treated individuals exposed to an inflammatory activator and or tumor cells. Such in vitro assays are well established and used in pre- and clinical science. Filed October 18, 2024 Example 4: Testing effectiveness of human-only CD47 morpholinos in lowering CD47 protein in various human cell types. [0303] Human-only cell-penetrating peptide conjugated CD47 morpholinos, DG9-CD47-A (SEQ ID NO: 21), DG9-CD47-B (SEQ ID NO: 26), DG9-CD47-C (SEQ ID NO: 22), and DG9-CD47-D (SEQ ID NO: 23), were tested for their ability to lower CD47 protein in human renal tubular epithelial cells, human T cells, and human breast cancer cells. [0304] Human-only cell-penetrating peptide conjugated CD47 morpholino oligonucleotides DG9- CD47-A, DG9-CD47-B, DG9-CD47-C, and DG9-CD47-D, effectively and at low concentrations lowered CD47 protein in human renal tubular epithelial cells. A non-species specific CD47 morpholino was previously reported to lower CD47 protein (Isenberg et al., Arterioscler Thromb Vasc Biol.2008 Apr; 28(4):615-21). However, the lack of target specificity of that prior morpholino resulted in less effectiveness. That is, it did not lower CD47 protein levels at the same concentrations as the human-only CD47 morpholinos provided herein, and could cause undesirable off-target effects. [0305] Human renal tubular epithelial cells were treated with several concentrations of the morpholino DG9-CD47-A (SEQ ID NO: 21) for 72 hours, and CD47 protein levels determined via Western blot (FIGs.19 and 20). The morpholino was effective at decreasing CD47 protein and at concentrations found effective at protecting normal non-cancer cells from genotoxic stress while rendering tumors susceptible to increased killing. Thus, the human-only CD47 morpholino was non-toxic and lowered CD47 protein in human cells. The CD47 morpholino is more effective than any prior published CD47 sequence in lowering CD47 protein (Isenberg et al., Circ Res. 2007 Mar 16;100(5):712-20). [0306] Given the position CD47 occupies in cell homeostasis, the targeting of CD47 ought to be done with care. Overly aggressive and rapid fluxes in CD47 protein levels induce cell death (Leslie et al., Diabet Med.38(12): e14724, 2021). This includes both suppression of CD47 protein or its forced over-expression as is being contemplated and tested in transplant settings to try to “cloak” transplanted cells from the immune system (Shrestha et al., Am J Transplant. 20(10):2703-2714, 2020). MATERIALS AND METHODS [0307] Human renal epithelial cells (3.5x10⁴) were harvested following 72 hours exposure to a cell-penetrating conjugated CD47 morpholino or vehicle. Cells were then lysed using 1xRIPA Buffer (Millipore, 20-188) plus phosphatase and protease inhibitors (Roche, 11836170001 and 04906845001). Protein concentration was measured using Pierce Rapid Gold BCA Protein Assay kit (ThermoFisher, A53226).50 µg of protein per sample was resolved by electrophoresis on Bolt 4-12% Bis-tris Plus (Invitrogen, NW04122BOX), transferred to nitrocellulose membranes, and Filed October 18, 2024 incubated with blocking buffer (5% milk in TBST) for 30 minutes at room temperature (RT), followed by primary antibodies at RT for 2 hours. Membranes were incubated with IRDye 800CW secondary antibodies (goat anti mouse 800CW # C90917-25, goat anti rabbit 800CW # C80718- 15) for 1 hour at RT. Imaging was performed using an Odyssey Sa Infrared Imaging system. Studies were repeated at least 3 times. Representative data is presented. [0308] Treatment with 1, 3, and 6 µM of the other CD47 morpholinos sequences showed that similar of concentration-dependent suppression of CD47 protein was obtained in primary human renal tubular epithelial cells treated with human-only morpholino sequences DG9-CD47-B (SEQ ID NO: 26), DG9-CD47-C (SEQ ID NO: 22), and DG9-CD47-D (SEQ ID NO: 23) (FIGs.19-22). DG9-CD47-B is a splice blocker and DG9-CD47-A, DG9-CD47-C, and DG9-CD47-D are translation blockers. That CD47 protein was decreased via targeting the pre-RNA and mature mRNA is a powerful internal control and further confirmation that the morpholinos were targeting only CD47. Relevant to this disclosure, the other cell-penetrating peptides, when conjugated to a CD47 morpholino, also suppressed CD47 protein without cell toxicity (FIGs.34 and 35). The findings that DG9-CD47-B (SEQ ID NO: 26; DG9-AGCGAGGAGCCACTCACCGCAGCAC, a splice blocking sequence; CD47-202 e1i1) suppressed CD47 protein is a large step forward in targeting CD47 in human primary cell types. This result was surprising. [0309] A human-only cell-penetrating peptide conjugated CD47 morpholino oligonucleotide effectively and at low concentrations lowered CD47 protein in human immune T cells. CD47 morpholino therapy may work, in part, by lowering protein levels in immune cells to maximize their cancer killing properties. Human T cells were treated with a concentration range of the human only morpholino DG9-CD47-A (SEQ ID NO: 21) and protein levels were determined. As with primary adherent human renal tubule epithelial cells, the morpholino suppressed total CD47 protein levels in human T CD4+ CD8+ cells (FIGs.15-18). This demonstrates that the morpholino was effective against non-adherent circulating immune cells. Second, the data shows that concentrations in the same range were effective at lowering CD47 protein in primary human cells from different distinct cell lineages. These data point to broad applicability of the herein provided CD47 morpholinos to many human cell types. [0037] A similar of concertation-dependent suppression of CD47 protein was obtained in human immune T cells treated with human-only morpholino sequences DG9-CD47-B (SEQ ID NO: 24), DG9-CD47-C (SEQ ID NO: 22), and DG9-CD47-D (SEQ ID NO: 23). MATERIALS AND METHODS [0310] Human T cells were treated with human-only cell-penetrating peptide conjugated CD47 morpholino oligonucleotide at the indicated concentrations or vehicle for 72 hours. Cell lysate was prepared using 1xRIPA Buffer (Millipore, 20-188) plus phosphatase and protease inhibitors (Roche, 11836170001 and 04906845001). Protein concentration was measured using Pierce Filed October 18, 2024 Rapid Gold BCA Protein Assay kit (ThermoFisher, A53226). 50 µg of protein per sample was resolved by electrophoresis on Bolt 4-12% Bis-tris Plus (Invitrogen, NW04122BOX), transferred to nitrocellulose membranes, and incubated with blocking buffer (5% milk in TBST) for 30 minutes at RT, followed by primary antibodies at RT for 2 hours. Membranes were incubated with IRDye 800CW secondary antibodies (goat anti mouse 800CW # C90917-25, goat anti rabbit 800CW # C80718-15) for 1 hour at RT. Imaging was performed using an Odyssey Sa Infrared Imaging system. Studies were repeated at least three times. Representative data is presented. [0311] A human-only cell-penetrating peptide conjugated CD47 morpholino oligonucleotide lowered CD47 in human cancer cells. It was not clear what effect the human-only CD47 morpholinos would have on human cancer cells. Human breast cancer cells were treated with the splice blocking morpholino DG9-CD47-B (SEQ ID NO: 24) for 72 hours and CD47 protein levels were determined via Western blot. Interestingly, CD47 levels were decreased in the cancer cells, and non-cancer cells. The other modified CD47 morpholinos also lowered total CD47 protein levels in the cancer cells (FIGs.23-26). This may enable selective targeting of therapeutic effect. Additionally, this study confirmed the effectiveness of the CD47 splice blocking morpholino and the theoretical use of this approach to alter CD47. These data open up a new group of morpholinos for application to human disease. MATERIALS AND METHODS [0312] MDA-Mb-231 breast cancer cells were treated for 72 hours with several concentrations of DG-9-CD47-B (SEQ ID NO: 26) or vehicle and lysates prepared using 1xRIPA Buffer (Millipore, 20-188) plus phosphatase and protease inhibitors (Roche, 11836170001 and 04906845001). Protein concentration was measured using Pierce Rapid Gold BCA Protein Assay kit (ThermoFisher, A53226).50 µg of protein per sample was resolved by electrophoresis on Bolt 4- 12% Bis-tris Plus (Invitrogen, NW04122BOX), transferred to nitrocellulose membranes, and incubated with blocking buffer (5% milk in TBST) for 30 minutes at RT, followed by primary antibodies at RT for 2 hours. Membranes were incubated with IRDye 800CW secondary antibodies (goat anti mouse 800CW # C90917-25, goat anti rabbit 800 CW # C80718-15) for 1 hour at RT. Imaging was performed using Odyssey Sa Infrared Imaging system. [0313] A human-only cell-penetrating peptide conjugated CD47 morpholino oligonucleotide decreased levels of cell surface CD47 in human cells. The effects of the new agents were demonstrated in cells with extended life. Indeed, a human only cell-penetrating conjugated CD47 morpholino lowered total CD47 protein in cancer cells. However, it was not known if lowering of total protein manifested coincided with changes in the levels of cell surface CD47. This is an important question in seeking to better understand the mechanism of action of CD47 morpholinos. CD47 is a checkpoint hub. Displayed on the cell surface of immune cells, CD47 acts in a trans manner with immune cell surface SIRPα to limit immune cell attack (Oldenborg et Filed October 18, 2024 al., Science.288(5473):2051-4, 2000; Oldenborg et al., J Exp Med.2001 Apr 2;193(7):855-62). Loss of cell surface CD47 may permit immune attack of cancer cells. This is supported by previously published reports that the cis CD47-SIRPα suppresses inflammation (Londino et al., J Biol Chem.290(52):31113-25, 2015). Thus, loss of the cis CD47-SIRPα signal increases tumor cell inflammatory signals to increase immune cell activation and tumor killing. However, the level of cell surface CD47 will be influenced by the turnover rate of the protein, possible cytoplasmic pools of mature protein, and the rate at which it is placed on and taken off the membrane. Human immune T cells were treated with the translation blocking morpholino DG9-CD47-A for 72 hours and cell surface CD47 protein levels were determined via flow cytometry. Interestingly, cell surface CD47 levels were decreased in the treated cells (FIGs.27 and 28). Cells treated with the control morpholino showed no decrease in cell surface CD47 protein. These data provide mechanistic insight in the therapeutic actions of the CD47 morpholinos and as a method to enhance cancer killing without inciting autoimmune injury of non-cancer cells. MATERIALS AND METHODS [0314] Human T cells were incubated in standard culture medium with translation blocking morpholino DG9-CD47-A (SEQ ID NO: 21) or control morpholino (NC705) (1 and 5 µM) for 72 hours and then cell surface CD47 protein levels determined via flow cytometry. Example 5: Testing cytotoxicity of cell uptake-enhanced, human-only CD47 morpholinos. [0315] Cell uptake-enhanced, human-only CD47 morpholinos DG9-CD47-A (SEQ ID NO: 21) and DG9-CD47-C (SEQ ID NO: 22) were tested for its effect on cell viability in human renal tubular epithelial cells. [0316] Human-only uptake-enhanced cell-penetrating peptide conjugated CD47 morpholino oligonucleotide, DG9-CD47-A, was not toxic to human renal tubular epithelial cells. To date, all CD47 morpholinos employed in cell and animal studies were used in a naked state, unconjugated to cell penetrating peptide(s). As the morpholino molecule is neutral in charge it has only modest cell membrane up-take. Such naked morpholinos required physical stress or proprietary soluble reagents to enhance morpholino uptake by mammalian cells, including human cells. However, such research grade methods of increasing cell uptake of morpholinos are not suitable for the clinic and human beings. Cell-penetrating peptides have a track record of clinical use to enhance cell uptake of various molecule. Herein, validated cell-penetrating peptides were added to the CD47 morpholino 3` end. The peptides were known to increase cell uptake of morpholinos (Shadid et al., Expert Opin Drug Metab Toxicol. 2021 Nov;17(11):1281-1292; Moulton HM. Pharm Des.2013;19(16):2963-9). Human renal tubular epithelial cells and human aortic arterial smooth muscle cells were treated with the cell-penetrating peptide conjugated CD47 morpholino (DG9-CD47-A) and found that there was no effect on cell viability at concentrations in the range Filed October 18, 2024 that may or will be employed clinically (FIGs.7, 10, and 11) and which markedly decrease CD47 protein levels. Likewise, morpholinos DG9-CD47-B (SEQ ID NO: 26), -C (SEQ ID NO: 22), and - D (SEQ ID NO: 23) were not cytotoxic at concentrations that lower CD47 protein (1-10 µM). As expected, excessively high concentrations of morpholino (20-25 µM) that would not be used therapeutically decreased cell viability, likely due to rapid and or near complete loss of CD47 which was reported to damage primary cells. MATERIALS AND METHODS [0317] Human renal tubular epithelial cells were seeded at 5x10³ and kept at 37°C overnight. Cells were treated the next day with DG9-CD47-A (SEQ ID NO: 21) for 72 hours. Cell-Titer Glo (G7571) was added to cells according to manufacturer’s protocol and cell viability was analyzed by luminometer. Studies were repeated at least 3 times. Representative data is presented. [0318] A human-only cell-penetrating peptide conjugated CD47 morpholino oligonucleotide (DG9-CD47-C; SEQ ID NO: 22) was nontoxic to human renal tubular epithelial cells and stimulated cell growth. Primary human renal tubular cells were treated with the cell-penetrating peptide conjugated CD47 morpholino (DG9-CD47-C) at several concentrations and found no effect on cell viability (FIG.14). Interestingly, treated cells showed proliferation/cell growth. This is not unexpected as CD47 acts to decrease cell growth. This data is shown to further emphasize the cell protective aspects of the morpholinos on primary cells. However, in cancer cells the CD47 morpholinos DG9-CD47-A (SEQ ID NO: 21) and -B (SEQ ID NO: 26) are directly cytotoxic (FIGs. 12 and 13), and did not stimulate cell proliferation/growth. Cell type specificity of this kind has not been previously reported for a CD47 morpholino, namely a pro-growth effect in primary cells and a direct cell killing in cancer cells. MATERIALS AND METHODS [0319] Human renal tubular epithelial cells were seeded at 5x10³ and kept at 37° C overnight. Cells were treated the next day with DG9-CD47-C (SEQ ID NO: 22) for 72 hours. Cell-Titer Glo (G7571) was added to cells according to the manufacturer protocol and cell viability was analyzed by luminometer. Studies were repeated at least 3 times. Representative data is presented. Example 6: Testing mitigation of chemotherapy-mediated cell killing by human-only CD47 morpholinos [0320] Human-only cell-penetrating peptide conjugated CD47 morpholinos (SEQ ID NOs: 21, 22, 23, 26) were tested for providing human T cells and renal tubular epithelial cells resistance to and protection from chemotherapy-mediated cell killing. [0321] A human-only cell-penetrating peptide conjugated CD47 morpholino oligonucleotide mitigated chemotherapy-mediated cell killing in human immune T cells. The treatment Filed October 18, 2024 advantages obtained from CD47 morpholinos in general include protection of non-cancer cells, including immune cells, tissues, and organs from genotoxic stress. Human T cells were treated with the human only CD47 morpholino + Doxorubicin. As noted, cell viability was improved in CD47 morpholino treated cells despite concurrent treatment with cytotoxic Doxorubicin (FIGs. 29-33). Other human-only morpholino sequences also conferred dose-dependent protection upon human T cells to Doxorubicin-mediated cell death. Thus, the human-only CD47 morpholinos provided to human immune T cells immunity and resistance to genotoxic stress. [0322] In these studies, the CD47 morpholino was given at the same time as the chemotherapy agent. These data show that the human-only CD47 morpholinos have therapeutic properties even if administered at the same time as exposure to the chemotherapeutic genotoxic stress. Especially noteworthy is the effectiveness of the morpholino to limit cell death at low concentrations (1-5 µM). Related to this, Doxorubicin can kill cells within 3 hours (Lüpertz et al., Toxicology. 271(3):115-21, 2010). The results of the CD47 morpholino/Doxorubicin studies described herein show for the first time that a CD47 morpholino is effective in relation to the almost immediate cell killing activity of the chemotherapy agent. MATERIALS AND METHODS [0323] Human T cells were seeded at 5x10³ and kept at 37° C overnight. Cells were treated the next day with DG9-CD47-D (SEQ ID NO: 23) at several concentrations + Doxorubicin for 72 hours. Cell-Titer Glo (G7571) was added to cells according to the manufacturer protocol and cell viability was analyzed by luminometer. [0324] A human-only cell-penetrating peptide conjugated CD47 morpholino oligonucleotide mitigated chemotherapy-mediated cell killing in human renal tubular epithelial cells. It was found that the morpholino preserved immune cells against chemotherapy. Expanding on this, human renal cells were treated with the human only CD47 morpholino + Doxorubicin. As noted, chemotherapy-mediated cell growth suppression/killing was markedly abrogated in CD47 morpholino treated cells (FIGs.32 and 33). Thus, both adherent matrix-bound cells (renal tubular epithelium) and circulating blood cells (immune T cells) were protected from genotoxic chemotherapy cell death. These data further confirm the enhanced efficiency of the described CD47 morpholinos as treatment was concurrent with Doxorubicin administration. [0325] These data can have very important implications. First, Dai et al. (Sci Immunol.2017 Jun 23;2(12): eaam6202) and others showed that the amount of CD47-SIRPα interaction is important to controlling macrophage activity. This may be true for the binding affinities of both ectodomains to each other as well as for the actual copy number of each ectodomain on the cell surface (Suter et al., Cell Rep.2021 Aug 24;36(8):109587). Thus, graded lowering of cell surface CD47 may yield a range of macrophage activities. The human-only CD47 morpholino was shown herein to lower cell surface CD47 in a stepwise fashion. Thus, it may not only protect macrophages from Filed October 18, 2024 the cell depleting and killing activities of genotoxic stress, but also act like a checkpoint blocker to enhance macrophage activity towards cancer cells via relative lowering of total CD47 signal. [0326] Second, suppression of CD47 in cancer cells will drive cell killing through activating damaging autophagy in cancer cells. More specifically, as shown in Maxhimer et al. (Sci Transl Med. Oct 21;1(3):3ra7, 2009) and (Soto-Pantoja et al., J Genet Syndr Gene Ther. 2011 Oct;2(2):1000105), suppression of CD47 under genotoxic stress turns on protective autophagy in primary non-cancer cells while at the same time activating cell killing autophagy in cancer cells. This divergent activity that discriminates between non-cancer cells, tissues, and organs and cancers is important to CD47 morpholino technology. Example 7: Representative Therapeutic Applications. [0327] The herein-described human-only cell-penetrating conjugated CD47 morpholinos will find therapeutic application in many conditions including (1) cancer alone and/or in combination with radiation, chemotherapy, checkpoint blocking molecules, CART cells, and/or other cancer therapies such as primary oncologic surgery, (2) radiation mitigation separate from its application in cancer (Soto-Pantoja et al., Sci Rep. 2013;3:1038), (3) cardiovascular diseases including hypertension (Bauer et al., Cardiovasc Res. 2010 Dec 1;88(3):471-81; Isenberg et al., Matrix Biol.2009 Mar;28(2):110-9; Labrousse-Arias et al., Cardiovasc Res.2016 Jan 1;109(1):115-30), peripheral arterial vascular disease (Rogers et al., Ann Surg.2013 Jul;258(1):184-91; Isenberg et al., Circ Res.2007 Mar 16;100(5):712-20; Isenberg et al., Arterioscler Thromb Vasc Biol.2007 Dec;27(12):2582-8; Isenberg et al., Ann Surg.2008 May;247(5):860-8), coronary artery disease, and stroke (Csányi et al., Arterioscler Thromb Vasc Biol.2012 Dec;32(12):2966-73), (4) left sided heat failure and other heart diseases (Sharifi-Sanjani et al., J Am Heart Assoc.2014 Jun 10;3(3): e000670; Procter et al., Int J Cardiol. 2015 Jan 20;179: 160-5; Procter et al., Herz. 2016 Feb;41(1):57-62; Procter et al., Am J Cardiovasc Dis. 2015 Aug 1;5(2):101-9), (5) pulmonary hypertension and right sided heart failure (Rogers et al., Cardiovasc Res.2017 Jul 1;113(8):858- 868; Rogers et al., Pulm Circ. 2013 Dec;3(4):936-51; Bauer et al., Cardiovasc Res. 2012 Mar 15;93(4):682-93), (6) sickle cell disease (Novelli et al., Am J Physiol Lung Cell Mol Physiol.2019 Jun 1;316(6): L1150-L1164; Jacob et al., Am J Hematol.2017 Mar;92(3): E31-E34; Novelli et al., Haematologica.2013 Nov;98(11): e132-4; Novelli et al., Am J Hematol.2012 Mar;87(3):326-30), (7) other hemoglobinopathies, (8) transplantation of visceral organs such as lungs, liver, kidneys (Rogers et al. J Am Soc Nephrol. 2012 Sep;23(9):1538-50; Rogers et al., Kidney Int. 2016 Aug;90(2):334-347) and others (Isenberg et al., Surgery. 2008144(5):752-61), (9) cell therapy such as islet transplantation for type 1 diabetes of and cell therapy; (10) bone marrow transplantation when used for malignant and non-malignant diseases, metabolic diseases such as diabetes (Wang et al., Am J Physiol Endocrinol Metab. 305(12): E1464-72, 2013) and (11) metabolic syndrome (Ghimire et al., Cells.9(7):1695, 2020), and (12) skin graft healing (Isenberg Filed October 18, 2024 et al., Ann Surg.247(1):180-90, 2008) and (13) wound healing of soft tissues (Isenberg et al., Nitric Oxide.21(1):52-62, 2009; Maxhimer et al., Plast Reconstr Surg.124(6):1880-1889, 2009) and bone (Zondervan et al., bioRxiv. 6:2024.03.06.583756, 2024). The agents may also find applications as additives to implantable devices such as vascular stents where the CD47 morpholino may slowly release and interact with endothelial cells and immune cells to limit pathologic remodeling of blood vessels and to stimulate angiogenesis, properties that were shown to be inherent to a CD47 morpholino (Isenberg et al., Circ Res. Mar 100(5):712-20, 2007) or nanoparticles. The technologies may also be useful to treat metabolic disorders and obesity. [0328] It has been shown that loss of CD47 in rodents improved mitochondrial function and exercise capacity and limited age-related adiposity (Frazier et al., Matrix Biol. 30(2):154-61, 2011). It was also found that targeting CD47 in rodents improved glucose balance in rodents on a high fat diet (Ghimire et al., Cells. 9(7):1695, 2020). Beyond the uses for various metabolic related diseases, the CD47 morpholinos may find some benefit as performance enhancers for elite athletes. XVII. References 1. 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Science.2000 Jun 16;288(5473):2051-4. doi: 10.1126/science.288.5473.2051. PMID: 10856220. Oldenborg PA, Gresham HD, Lindberg FP. CD47-signal regulatory protein alpha (SIRPalpha) regulates Fcgamma and complement receptor-mediated phagocytosis. J Exp Med. 2001 Apr 2;193(7):855-62. doi: 10.1084/jem.193.7.855. PMID: 11283158; PMCID: PMC2193364. Suter EC, Schmid EM, Harris AR, Voets E, Francica B, Fletcher DA. Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation. Cell Rep. 2021 Aug 24;36(8):109587. doi: 10.1016/j.celrep.2021.109587. PMID: 34433055; PMCID: PMC8477956. Rogers NM, Roberts DD, Isenberg JS. Age-associated induction of cell membrane CD47 limits basal and temperature-induced changes in cutaneous blood flow. Ann Surg.2013 Jul;258(1):184-91. doi: 10.1097/SLA.0b013e31827e52e1. PMID: 23275312; PMCID: PMC3626753. Csányi G, Yao M, Rodríguez AI, Al Ghouleh I, Sharifi-Sanjani M, Frazziano G, Huang X, Kelley EE, Isenberg JS, Pagano PJ. Thrombospondin-1 regulates blood flow via CD47 receptor-mediated activation of NADPH oxidase 1. Arterioscler Thromb Vasc Biol.2012 Dec;32(12):2966-73. doi: 10.1161/ATVBAHA.112.300031. Epub 2012 Oct 18. PMID: 23087362; PMCID: PMC4394361. Rogers NM, Zhang ZJ, Wang JJ, Thomson AW, Isenberg JS. CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion. Kidney Int. 2016 Aug;90(2):334-347. doi: 10.1016/j.kint.2016.03.034. Epub 2016 Jun 1. PMID: 27259369. Rogers NM, Ghimire K, Calzada MJ, Isenberg JS. Matricellular protein thrombospondin- 1 in pulmonary hypertension: multiple pathways to disease. Cardiovasc Res. 2017 Jul 1;113(8):858-868. doi: 10.1093/cvr/cvx094. PMID: 28472457; PMCID: PMC5852507. Rogers NM, Yao M, Sembrat J, George MP, Knupp H, Ross M, Sharifi-Sanjani M, Milosevic J, St Croix C, Rajkumar R, Frid MG, Hunter KS, Mazzaro L, Novelli EM, Stenmark KR, Gladwin MT, Ahmad F, Champion HC, Isenberg JS. Cellular, pharmacological, and biophysical evaluation of explanted lungs from a patient with sickle cell disease and severe pulmonary arterial hypertension. Pulm Circ.2013 Dec;3(4):936- 51. doi: 10.1086/674754. PMID: 25006410; PMCID: PMC4070844. Jacob SA, Novelli EM, Isenberg JS, Garrett ME, Chu Y, Soldano K, Ataga KI, Telen MJ, Ashley-Koch A, Gladwin MT, Zhang Y, Kato GJ. Thrombospondin-1 gene polymorphism is associated with estimated pulmonary artery pressure in patients with sickle cell anemia. Am J Hematol. 2017 Mar;92(3): E31-E34. doi: 10.1002/ajh.24635. Epub 2017 Feb 3. PMID: 28033687; PMCID: PMC5303556. Novelli EM, Kato GJ, Hildesheim ME, Barge S, Meyer MP, Lozier J, Hassett AC, Ragni MV, Isenberg JS, Gladwin MT. Thrombospondin-1 inhibits ADAMTS13 activity in sickle Filed October 18, 2024 cell disease. Haematologica. 2013 Nov;98(11): e132-4. doi: 10.3324/haematol.2013.092635. PMID: 24186313; PMCID: PMC3815185. 103. Procter NE, Ball J, Liu S, Hurst N, Nooney VB, Goh V, Stafford I, Heresztyn T, Carrington M, Ngo DT, Hylek EM, Isenberg JS, Chirkov YY, Stewart S, Horowitz JD; SAFETY Investigators. Impaired platelet nitric oxide response in patients with new onset atrial fibrillation. Int J Cardiol.2015 Jan 20;179: 160-5. doi: 10.1016/j.ijcard.2014.10.137. Epub 2014 Oct 23. PMID: 25464437. 104. Procter NE, Ball J, Ngo DT, Chirkov YY, Isenberg JS, Hylek EM, Stewart S, Horowitz JD. Platelet hyperaggregability in patients with atrial fibrillation. Evidence of a background proinflammatory milieu. Herz. 2016 Feb;41(1):57-62. doi: 10.1007/s00059-015-4335-y. Epub 2015 Jul 2. PMID: 26135468. 105. Procter NE, Ball J, Heresztyn T, Nooney VB, Liu S, Chong CR, Ngo DT, Isenberg JS, Chirkov YY, Stewart S, Horowitz JD. Subtle renal dysfunction and bleeding risk in atrial fibrillation: symmetric dimethylarginine predicts HAS-BLED score. Am J Cardiovasc Dis. 2015 Aug 1;5(2):101-9. PMID: 26309773; PMCID: PMC4539096. 106. Wang JM, Isenberg JS, Billiar TR, Chen AF. Thrombospondin-1/CD36 pathway contributes to bone marrow-derived angiogenic cell dysfunction in type 1 diabetes via Sonic hedgehog pathway suppression. Am J Physiol Endocrinol Metab. 2013 Dec;305(12): E1464-72. doi: 10.1152/ajpendo.00516.2013. Epub 2013 Oct 22. PMID: 24148348; PMCID: PMC3882377. 107. Hu X, Gattis C, Olroyd AG, Friera AM, White K, Young C, Basco R, Lamba M, Wells F, Ankala R, Dowdle WE, Lin A, Egenberger K, Rukstalis JM, Millman JR, Connolly AJ, Deuse T, Schrepfer S. Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice. Sci Transl Med.2023 Apr 12;15(691): eadg5794. 108. Londino JD, Gulick D, Isenberg JS, Mallampalli RK. Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling. J Biol Chem. 2015 Dec 25;290(52):31113-25. doi: 10.1074/jbc.M115.682914. 109. Narkhede M, Bartlett NL, Ibrahimi S, Popplewell L, Seto A, Bates J, Lee Y, Ganti V, Han L, Chen T, Patel MR. A phase 1 first-in-human study of GS-0189, an anti-signal regulatory protein alpha (SIRPα) monoclonal antibody, in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). EJHaem.2023 Apr 7;4(2):370-380 110. Lebleu B, Moulton HM, Abes R, Ivanova GD, Abes S, Stein DA, Iversen PL, Arzumanov AA, Gait MJ. Cell penetrating peptide conjugates of steric block oligonucleotides. Adv Drug Deliv Rev.2008 Mar 1;60(4-5):517-29. 111. Evans et al., An anionic, endosome-escaping polymer to potentiate intracellular delivery of cationic peptides, biomacromolecules, and nanoparticles. Nat Commun.201910:4012; doi.org/10.1038/s41467-019-12906-y 112. Zondervan RL, Capobianco CA, Jenkins DC, Reicha JD, Fredrick LM, Lam C, Isenberg JS, Ahn J, Marcucio RS, Hankenson KD. CD47 is Required for Mesenchymal Progenitor Proliferation and Fracture Repair. bioRxiv [Preprint].2024 Mar 6:2024.03.06.583756. XVIII. Closing Paragraphs [0329] As will be understood by one of ordinary skill in the art, each embodiment disclosed herein can comprise, consist essentially of or consist of its particular stated element, step, ingredient or component. Thus, the terms “include” or “including” should be interpreted to recite: “comprise, consist of, or consist essentially of.” The transition term “comprise” or “comprises” means has, but is not limited to, and allows for the inclusion of unspecified elements, steps, ingredients, or components, even in major amounts. The transitional phrase “consisting of” excludes any element, step, ingredient or component not specified. The transition phrase “consisting Filed October 18, 2024 essentially of” limits the scope of the embodiment to the specified elements, steps, ingredients or components and to those that do not materially affect the embodiment. [0330] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. When further clarity is required, the term “about” has the meaning reasonably ascribed to it by a person skilled in the art when used in conjunction with a stated numerical value or range, i.e. denoting somewhat more or somewhat less than the stated value or range, to within a range of ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±11% of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1% of the stated value. [0331] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. [0332] The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. Filed October 18, 2024 [0333] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims. [0334] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. [0335] Furthermore, numerous references have been made to patents, printed publications, journal articles, other written text, and web site content throughout this specification (referenced materials herein). Each of the referenced materials are individually incorporated herein by reference in their entirety for their referenced teaching(s), as of the filing date of the first application in the priority chain in which the specific reference was included. For instance, with regard to chemical compounds, nucleic acid, and amino acids sequences referenced herein that are available in a public database, the information in the database entry is incorporated herein by reference as of the date of an application in the priority chain in which the database identifier for that compound or sequence was first included in the text. [0336] It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described. [0337] The particulars shown herein are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of various embodiments of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for the fundamental understanding of the invention, the description taken with the drawings and/or Filed October 18, 2024 examples making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. [0338] Definitions and explanations used in the present disclosure are meant and intended to be controlling in any future construction unless clearly and unambiguously modified in the example(s) or when application of the meaning renders any construction meaningless or essentially meaningless. In cases where the construction of the term would render it meaningless or essentially meaningless, the definition should be taken from Webster's Dictionary, 11^th Edition or a dictionary or reference text known to those of ordinary skill in the art, such as the Oxford Dictionary of Biochemistry and Molecular Biology, 2^nd Edition (Ed. Anthony Smith, Oxford University Press, Oxford, 2006), A Dictionary of Chemistry, 8^th Edition (Ed. J. Law & R. Rennie, Oxford University Press, 2020), Green and Sambrook, Molecular Cloning: A Laboratory Manual, 4^th Edition (2012); F. M. Ausubel et al. eds., Current Protocols in Molecular Biology, (2003); the series Methods In Enzymology (Academic Press, Inc.); Behlke et al., Polymerase Chain Reaction: Theory and Technology (2019); Greenfield, ed. Antibodies, A Laboratory Manual, 2^nd Edition (2014); and Capes-Davis and Freshney, eds. Freshney's Culture of Animal Cells 8^th Edition (2021).

Claims

Filed October 18, 2024 LISTING OF CLAIMS What is claimed is: 1. A CD47 antisense morpholino oligonucleotide comprising a nucleic acid sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 (CD47-A’), SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47- 202_e10i10). 2. A CD47 antisense morpholino oligonucleotide comprising a nucleic acid with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47- C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 (CD47-A’), SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47- 202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47- 202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10). 3. The CD47 antisense morpholino oligonucleotide of claim 1 or claim 2, further comprising a cell-penetrating peptide (CPP) conjugated to the oligonucleotide. 4. The CD47 antisense morpholino oligonucleotide of claim 3, wherein the CPP is conjugated at the 5’ end of the oligonucleotide. 5. The CD47 antisense morpholino oligonucleotide of claim 3 or claim 4, comprising a sequence as shown in any one of SEQ ID NOs: 21-68. 6. A non-naturally occurring antisense oligonucleotide specific for human CD47, the sequence of which consists essentially of a sequence set forth in any of: SEQ ID NO: 1 (CD47- A); SEQ ID NO: 3 (CD47-C); SEQ ID NO: 4: (CD47-D); SEQ ID NO: 5: (CD47-E); SEQ ID NO: 16 (CD47-A’); SEQ ID NO: 2, CD47-B (CD47-202_e1i1); SEQ ID NO: 6, SB1 (CD47-202_e1i1’); SEQ ID NO: 7, SB2 (CD47-202_i1e2); SEQ ID NO: 8, SB3 (CD47-202_e2i2); SEQ ID NO: 9, SB4 (CD47-202_e4i4); SEQ ID NO: 10, SB5 (CD47-202_e5i5); SEQ ID NO: 11, SB6 (CD47- 202_i5e6); SEQ ID NO: 12, SB7 (CD47-202_e6i6); SEQ ID NO: 13, SB8 (CD47-202_e8i8); SEQ ID NO: 14, SB9 (CD47-202_i9e10); or SEQ ID NO: 15, SB10 (CD47-202_e10i10). Filed October 18, 2024 7. The non-naturally occurring antisense oligonucleotide of claim 6, which comprises at least one morpholino ring. 8. The non-naturally occurring antisense oligonucleotide of claim 6 or claim 7, further comprising a cell-penetrating peptide (CPP) conjugated to the oligonucleotide. 9. The non-naturally occurring antisense oligonucleotide of claim 8, wherein the CPP is conjugated at the 5’ end of the oligonucleotide. 10. The non-naturally occurring antisense oligonucleotide of claim 8, comprising a sequence as shown in any one of SEQ ID NOs: 21-68. 11. A hybrid nucleic acid-peptide fusion molecule comprising: an antisense oligonucleotide specific for human CD47, and comprising a nucleic acid sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 (CD47-A’), SEQ ID NO: 2, CD47-B (CD47- 202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47- 202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10); and a peptide covalently attached to the antisense oligonucleotide. 12. The fusion molecule of claim 11, wherein the peptide is covalently attached at the 5’ end of the antisense oligonucleotide. 13. The fusion molecule of claim 11, wherein the peptide comprises a cell penetrating peptide (CPP) or other cell targeting sequence. 14. The fusion molecule of claim 13, wherein the peptide comprises: DG9 YArVRRrGPRGYArVRRrGPRrB (SEQ ID NO: 18; r = D-arginine, B = beta-alanine); R6G: RRRRRRG (SEQ ID NO: 19); or r6G: rrrrrrG (SEQ ID NO: 20; r = D-arginine). 15. The fusion molecule of claim 13, comprising a sequence as shown in any one of SEQ ID NOs: 21-68. Filed October 18, 2024 16. A composition comprising: at least one therapeutic molecule selected from: the CD47 antisense morpholino oligonucleotide of any one of claims 1-5; the non-naturally occurring antisense oligonucleotide of any one of claims 6-10; or the hybrid nucleic acid-peptide fusion molecule of any one of claims 11-15; and at least one biologically or pharmaceutically acceptable excipient or carrier. 17. The composition of claim 16, formulated for delivery to a subject. 18. The formulated composition of claim 17, formulated to be delivered to the subject transdermally, intramuscularly, intravenously, by inhalation, or intranasally. 19. The composition of claim 16, comprising at least two of the therapeutic molecules. 20. The composition of claim 19, wherein the at least two therapeutic molecules comprise: at least one oligonucleotide with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), or SEQ ID NO: 16 (CD47-A’); and at least one oligonucleotide with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47- 202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10). 21. A composition comprising a plurality of different CD47 antisense morpholino oligonucleotides of any of claims 1-5. 22. A composition comprising a plurality of different non-naturally occurring antisense oligonucleotides of any one of claims 6-10. 23. A composition comprising a plurality of different hybrid nucleic acid-peptide fusion molecules of any one of claims 11-15. Filed October 18, 2024 24. The composition of any one of claims 20-23, wherein the at least two oligonucleotides or fusion molecules comprise: at least one oligonucleotide with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), or SEQ ID NO: 16 (CD47-A’); and at least one oligonucleotide with a sequence consisting of the sequence set forth in any of: SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47- 202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10). 25. A composition comprising a human-specific CD47-targeted antisense oligonucleotide, essentially as described herein. 26. The CD47 antisense morpholino oligonucleotide of any one of claims 1-5, the non- naturally occurring antisense oligonucleotide of any one of claims 6-10, the hybrid nucleic acid- peptide fusion molecule of any one of claims 11-15, or the composition of any one of claims 16- 25, for use in modulating CD47 signalling in a subject. 27. The CD47 antisense morpholino oligonucleotide of any one of claims 1-5, the non- naturally occurring antisense oligonucleotide of any one of claims 6-10, the hybrid nucleic acid- peptide fusion molecule of any one of claims 11-15, or the composition of any one of claims 16- 25, for use in a method of reducing cytotoxicity or genotoxicity of an agent in a subject. 28. A method comprising administering to a subject a CD47-level reducing amount of an agent selected from: the CD47 antisense morpholino oligonucleotide of any one of claims 1-5, the non-naturally occurring antisense oligonucleotide of any one of claims 6-10, the hybrid nucleic acid-peptide fusion molecule of any one of claims 11-15, or the composition of any one of claims 16-25. 29. The method of claim 28, which reduces at least one cytotoxic or at least one genotoxic effect of an agent in the subject. Filed October 18, 2024 30. The method of claim 28, wherein the agent comprises a chemotherapeutic agent, a radionuclide administered as part of a radiation treatment or other radiation exposure, or another cytotoxic or genotoxic agent administered to the subject. 31. The method of claims 28-30, wherein the agent is administered transdermally, intramuscularly, by inhalation, or intranasally. 32. A method of reducing cytotoxicity of a chemotherapeutic agent to non-cancer cells in a subject with cancer, comprising: administering to the subject an effective amount of a CD47 antisense morpholino oligonucleotide comprising the nucleic acid sequence set forth in any of: SEQ ID NO: 1 (CD47- A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 ID NO: CD47-B ID NO: SB1 , 9,

, , , ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10); and one or more chemotherapeutic agents, wherein the CD47 antisense morpholino inhibits CD47 signaling and is administered to the subject before, during, or after administration of the one or more chemotherapeutic agents. 33. The method of claim 32, wherein the CD47 antisense morpholino oligonucleotide further comprises a cell-penetrating peptide (CPP) conjugated to the oligonucleotide. 34. The method of claim 33, wherein the CPP is conjugated at the 5’ end of the oligonucleotide. 35. The method of claim 33, wherein the CD47 antisense morpholino oligonucleotide comprises a sequence as shown in any one of SEQ ID NOs: 21-68. 36. The method of claims 32-25, in which the CD47 antisense morpholino oligonucleotide is administered transdermally, intramuscularly, by inhalation, or intranasally. 37. A method of reducing cytotoxicity of a chemotherapeutic agent to non-cancer cells, comprising: (a) administering an effective amount of at least one CD47 morpholino oligonucleotide comprising the nucleic acid sequence set forth as in any of: SEQ ID NO: 1 (CD47-A), SEQ ID Filed October 18, 2024 NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), SEQ ID NO: 16 (CD47- A’), SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47- 202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47-202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47-202_e10i10) to a subject with cancer; (b) administering one or more chemotherapeutic agents to the subject with cancer, wherein (a) and (b) can be performed in either order or concurrently; and (c) detecting a reduction of cytotoxicity to non-cancer cells in the subject. 38. The method of claim 37, wherein the CD47 antisense morpholino oligonucleotide further comprises a cell-penetrating peptide (CPP) conjugated to the oligonucleotide. 39. The method of claim 38, wherein the CPP is conjugated at the 5’ end of the oligonucleotide. 40. The method of claim 38, wherein the CD47 antisense morpholino oligonucleotide comprises a sequence as shown in any one of SEQ ID NOs: 21-68. 41. The method of claims 37-40, wherein the CD47 antisense morpholino oligonucleotide is administered transdermally, intramuscularly, by inhalation, or intranasally. 42. The method of any one of claims 37-41, wherein the CD47 antisense morpholino oligonucleotide is delivered concurrently with the cytotoxic or genotoxic challenge. 43. The method of any one of claims 28-42, comprising administering at least one splice blocker oligonucleotide and at least one translation blocker oligonucleotide. 44. The method of claim 43, wherein: the at least one splice blocker oligonucleotide has a sequence consisting of the sequence set forth in any of: SEQ ID NO: 1 (CD47-A), SEQ ID NO: 3 (CD47-C), SEQ ID NO: 4: (CD47-D), SEQ ID NO: 5: (CD47-E), or SEQ ID NO: 16 (CD47-A’); and the at least one translation blocker oligonucleotide has a sequence consisting of the sequence set forth in any of: SEQ ID NO: 2, CD47-B (CD47-202_e1i1), SEQ ID NO: 6, SB1 (CD47-202_e1i1’), SEQ ID NO: 7, SB2 (CD47-202_i1e2), SEQ ID NO: 8, SB3 (CD47-202_e2i2), SEQ ID NO: 9, SB4 (CD47-202_e4i4), SEQ ID NO: 10, SB5 (CD47-202_e5i5), SEQ ID NO: 11, SB6 (CD47-202_i5e6), SEQ ID NO: 12, SB7 (CD47-202_e6i6), SEQ ID NO: 13, SB8 (CD47- Filed October 18, 2024 202_e8i8), SEQ ID NO: 14, SB9 (CD47-202_i9e10), or SEQ ID NO: 15, SB10 (CD47- 202_e10i10). 45. The method of claim 43 or claim 44, wherein the splice blocker oligonucleotide and/or the translation blocker oligonucleotide further comprises a cell penetrating peptide (CPP) conjugated thereto. 46. The method of claim 45, wherein the splice blocker oligonucleotide and/or the translation blocker oligonucleotide is selected from SEQ ID NOs: 21-68. 47. The method of any one of claims 28-46, wherein the subject is a human. 48. The method of claim 47, wherein the subject is immunocompromised. 49. The method of claim 47, wherein the therapeutic agent(s) is administered transdermally, intramuscularly, intravenously, by inhalation, or intranasally.