Methods of treating dystrophinopathies

Abstract

Described herein are compositions comprising neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPC secretomes, nMPC exosomes, or a combination thereof in treating a dystrophinopathy and / or a cardiomyopathy associated with a dystrophinopathy in a subject in need thereof. Non-limiting examples of dystrophinopathies which may be treated comprise Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), or dystrophinopathy-associated dilated cardiomyopathy (DCM). One or more doses of the neonatal cardiac mesenchymal progenitor cells, nMPC secretomes, nMPC exosomes, or a combination thereof, can be administered to the subject. Neonatal cardiac mesenchymal progenitor cells can be allogeneic. The subject may also be administered with an additional therapies.

Description

WSGR Ref. No.: 64320-710.601METHODS OF TREATING DYSTROPHINOP ATHIES CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 769,525, filed March 10, 2025, and U. S. Provisional Application No. 63 / 872,115, filed August 28, 2025, each of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Dystrophinopathies are a group of muscle disorders that affect the heart and muscles used for movement. They are caused by mutations in the various genes. There is an unmet need for treating patients with dystrophinopathies and cardiomyopathy in patients with dystrophinopathies.SUMMARY OF THE DISCLOSURE

[0003] Described herein, in certain aspects, are compositions comprising neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (nMPC conditioned medium), and / or nMPC exosomes, and uses thereof in the treatment of a dystrophinopathy. Described herein, in certain aspects, are compositions comprising neonatal cardiac mesenchymal progenitor cells (nMPCs) and uses thereof in the treatment of cardiomyopathy in subjects with a muscular dystrophy. Described herein, in certain aspects, are compositions comprising an nMPC secretome (an nMPC conditioned media) and / or nMPC exosomes in the treatment of cardiomyopathy in subjects with a dystrophinopathy. A dystrophinopathy can be a hereditary muscular dystrophy, an acquired muscular dystrophy, or an intermediate phenotype muscular dystrophy. Dystrophinopathies include, but are not limited to, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, a DMD-associated dilated cardiomyopathy (DCM), a limb-girdle muscular dystrophy (LGMD), a congenital muscular dystrophy, a congenital myopathy, a distal hereditary myopathy, a facioscapulohumeral muscular dystrophy (FSHD), an oculopharyngeal muscular dystrophy (OPMD), Emery-Dreifuss muscular dystrophy (EDMD), a congenital muscular dystrophy, a Congenital myopathy, a Myofibrillar myopathy, an Inclusion body myositis (IBM), a myotonic dystrophy, a metabolic myopathy, a mitochondrial myopathy, or an inflammatory myopathy. Treatment encompasses treatment of a symptom of a dystrophinopathy, wherein a “symptom” may also be referred to herein as a “pathological hallmark” of a disorder.

[0004] Described herein, in one aspect, is a method of treating a dystrophinopathy in a subject in need thereof, comprising administering to the subject neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (conditioned medium), nMPC exosomes, or any combination thereof, whereby the dystrophinopathy is treated. Described herein, in one aspect, is a method of treating cardiomyopathy associated with a dystrophinopathy in a subject in need thereof, comprising administering to the subject neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (conditioned medium), nMPC exosomes, or any combination thereof, whereby the cardiomyopathy is treated. In some embodiments, the cardiomyopathy is dilated cardiomyopathy. In some embodiments, the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positiveWSGR Ref. No.: 64320-710.601for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p16INK4a. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67 orNkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a. In another embodiment, the nMPCs are (a) positive for protein expression of Ki67 and Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, andp16INK4a. In certain embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2. In some embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2. Alternatively, or in addition, the nMPCs are further negative for protein expression of p16INK4aup to at least passage 8. In some embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p16INK4aIn certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative forprotein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or p16INK4a. In yet other embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a

[0005] In some embodiments, the nMPCs are genetically engineered. In other embodiments, the nMPCs are genetically engineered to overexpress one or more paracrine factors. In some embodiments, the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In some embodiments, the nMPCs are genetically engineered to overexpress 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / orWSGR Ref. No.: 64320-710.601S0X2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and p16INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPCs are allogeneic or autologous. In certain embodiments, the nMPCs are non-naturally occurring. In other embodiments, the nMPCs are not xenogenic. In some embodiments, the nMPCs are obtained from a subject who is biologically a female. In certain other embodiments, the nMPCs are obtained from a subject who is biologically a male.

[0006] In some embodiments, the nMPCs are: (a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2; (b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 ofc-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1; (c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4; and / or (e) negative for protein expression of p16INK4aup to at least passage 8. In one embodiment, the nMPCs are: (a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2; (b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1; (c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR- 374b- 5p; and (d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and p16INK4a. In some embodiments, the nMPCs express HSF1 at levels higher than adult mesenchymal progenitor cells (aMPCs). In some embodiments, the nMPCs are further negative for protein expression of IGF 1. In some instances, the nMPCs do not express 42254.

[0007] Alternatively, or in addition, described herein is a method of treating a dystrophinopathy in a subject in need thereof, comprising administering to the subject an nMPC secretome (conditioned medium) or nMPC exosomes. In another aspect, the subject is administered a composition comprising the nMPC secretome. In some embodiments, the nMPC secretome comprises cytokines, chemokines, hormones, digestive enzymes, antibodies, extracellular proteinases, morphogens, antimicrobial peptides, chaperone proteins, growth factors, miRNAs, extracellular vesicles (e.g., exosomes), or a combination thereof. In certain embodiments, the nMPC secretome is (a) positive for protein expression of HGF, SCF,WSGR Ref. No.: 64320-710.601SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPC secretome is (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. In another embodiment, the nMPC secretome is (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and Akt, and (b) positive formiRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPC secretome is positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p.

[0008] Alternatively, or in addition, in certain embodiments, the nMPC secretome is positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUMO1, EIF3A, ECHI, HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RAB1A, RAB1B, PGRMC1, ERH, TIGAR, ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP100, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY1, AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH, DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS, TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1, NMT2, MAT2A, PRMT1, COX17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RABI 1 A, RABI IB, EIF5, COPZ1, COPS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2, TOMI, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2, TRIP10, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9, MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, OS9, ILF3, ISOC1, PPP1R7, MAPK1, PDCD1LG2, GOLGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orfl66, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14, PLAUR, CXCL3, FASN, COPB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, COL16A1,WSGR Ref. No.: 64320-710.601PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TR0VE2, MACF1, EIF5B, STX7, PFDNS, AP0A1, PDAP1, STX12, EIF3K, FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK / 7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28, PPIC, NARS, PCBP2, CD2AP, PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1, MANI Al, DDB1, PTBP1, FBN2, CNBP, OTUB1, NASP, HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS, ILF2, COPB1, PA2G4, COP A, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, and EPB41L3. Alternatively, or in addition, in certain embodiments, the nMPC secretome is positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of PPP1CA, PPP1CC, ST13, ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, NEDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TP M3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, EN01, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPA0, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, and PAFAH1B2.

[0009] In some embodiments, the nMPC secretome comprises a final protein concentration of from about 0.1 mg / ml to about 50.0 mg / ml, or from about 0.5 mg / ml to about 20.0 mg / ml. In some embodiments, the nMPC secretome comprises a final protein concentration of (a) at least about 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, about 2.0 mg / ml, about 3.0 mg / ml, about 4.0 mg / ml, about 5.0 mg / ml, about 6.0 mg / ml, about 7.0 mg / ml, about 8.0 mg / ml, about 9.0 mg / ml, about 10.0 mg / ml, about 11.0 mg / ml, about 12.0 mg / ml, about 13.0 mg / ml, about 14.0 mg / ml, about 15.0 mg / ml, about 16.0 mg / ml, about 17.0 mg / ml, about 18.0 mg / ml, about 19.0 mg / ml, about 20.0 mg / ml, about 22.0 mg / ml, about 24.0 mg / ml, about 26.0 mg / ml, about 28.0 mg / ml, about 30.0 mg / ml, about 35.0 mg / ml, about 40.0 mg / ml, about 45.0 mg / ml, or about 50.0 mg / ml, or (b) at most about 250.0 mg / ml, about 225.0 mg / ml, about 200.0 mg / ml, about 175 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 75 mg / ml, about 50 mg / ml, about 45.0 mg / ml, about 40.0 mg / ml, about 35.0 mg / ml, about 30.0 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, about 1 mg / ml, about 0.5 mg / ml, or about 0.1 mg / ml. In some embodiments, the nMPC secretome comprises a final protein concentration of at least about 1.0 mg / ml±0.5. In other embodiments, the nMPC secretome comprises a final protein concentration of at least about 4.0 mg / ml±1.0. In some embodiments, the nMPC secretome comprises a final protein concentration of at least about 8.0 mg / ml±2.0. In yet other embodiments, the nMPC secretome comprises a final protein concentration of at least about 16.0 mg / ml±3.0.

[0010] In one aspect, compositions comprise nMPC exosomes. In another aspect, the subject is administered a composition comprising the nMPC exosomes. In some embodiments, the nMPC exosomes comprise a transmembrane protein, tetraspanin, antigen presenting molecule, glycoprotein,WSGR Ref. No.: 64320-710.601adhesion molecule, heat shock protein (Hsp), cytoskeletal protein, ESCRT component, membrane transport protein, fusion protein, growth factor, cytokine, lipid, Fas ligand (FasL), mRNA, miRNA, noncoding RNA, DNA, TNF receptor, or transferrin receptor (TfR), or a combination thereof. In some embodiments, the lipid comprises cholesterol, ceramides, sphingomyelin, phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylethanolamine (PE), gangliosides (GM), or a combination thereof. In some embodiments, the nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. In another embodiment, the nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and Akt, and (b) positive formiRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPC exosomes are positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPC exosomes are positive for protein expression of CD81 and / or CD63. In some embodiments, the nMPC exosomes are positive for protein expression of CD81 and CD63.

[0011] Alternatively, or in addition, in some embodiments, nMPC exosomes are positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUMO1, EIF3A, ECHI, HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RAB1A, RAB1B, PGRMC1, ERH, HGAR, ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP100, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY1, AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH, DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS, TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1, NMT2, MAT2A, PRMT1, COX17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RABI 1 A, RABI IB, EIF5, COPZ1, COPS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2, TOMI, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2,WSGR Ref. No.: 64320-710.601TRIPIO, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9, MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, OS9, ILF3, ISOC1, PPP1R7, MAPK1, PDCD1LG2, GOLGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orfl66, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14, PLAUR, CXCL3, FASN, COPB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, COL16A1, PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TROVE2, MACF1, EIF5B, STX7, PFDNS, APOA1, PDAP1, STX12, EIF3K, FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28, PPIC, NARS, PCBP2, CD2AP, PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1, MANI Al, DDB1, PTBP1, FBN2, CNBP, OTUB1, NASP, HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS, ILF2, COPB1, PA2G4, COP A, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, or EPB41L3. Alternatively, or in addition, in some embodiments, the nMPC exosomes are positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of PPP1CA, PPP1CC, ST13, ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, NEDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, ENO1, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPA0, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, and PAFAH1B2.

[0012] In some embodiments, the nMPC exosomes comprise particles in a range of from about 50 nm to about 1000 nm, about 100 nm to about 1000 nm, about 500 nm to about 1000 nm, about 600 nm to about 900 nm, about 700 nm to about 800 nm, about 300 nm to about 600 nm, about 300 nm to about 500 nm, 300 nm to about 400 nm, about 200 nm to about 500 nm, 200 nm to about 400 nm, about 100 nm to about 500 nm, about 100 nm to about 300 nm, 100 nm to about 200 nm, 100 nm to about 150 nm, about 50 nm to about 200 nm, about 50 nm to about 150 nm, about 50 nm to about 110 nm, about 50 nm to about 100 nm, about 75 nm to about 250 nm, about 75 nm to about 200 nm, about 75 nm to about 150 nm, about 75 nm to about 100 nm, about 90 nm to about 150 nm, about 90 nm to about 125 nm, about 90 nm to about 110 nm, or about 90 nm to about 100 nm in diameter. In one embodiment, the nMPC exosomes comprise particles in a range of from about 90 nm to about 110 nm in diameter. In another embodiment, the nMPC exosomes comprise particles in a range of from about 100 nm to about 120 nm in diameter. In some embodiments, the nMPC exosomes comprise particles about 50 nm, 60 nm, 70 nm,WSGR Ref. No.: 64320-710.60180 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, or 1000 nm in diameter. In some embodiments, the nMPC exosomes comprise particles about 90 nm in diameter. In certain embodiments, the nMPC exosomes comprise particles about 100 nm in diameter. In other embodiments, the nMPC exosomes comprise particles about 110 nm in diameter. In yet other embodiments, the nMPC exosomes have a density of about 1.13 g / ml to about 1.19 g / ml.

[0013] In some embodiments, the nMPC exosomes comprise a final protein concentration of from about 0.1 mg / ml to about 50.0 mg / ml, or from about 0.5 mg / ml to about 20.0 mg / ml. In some embodiments, the nMPC exosomes comprise a final protein concentration of (a) at least about 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, about 2.0 mg / ml, about 3.0 mg / ml, about 4.0 mg / ml, about 5.0 mg / ml, about 6.0 mg / ml, about 7.0 mg / ml, about 8.0 mg / ml, about 9.0 mg / ml, about 10.0 mg / ml, about 11.0 mg / ml, about 12.0 mg / ml, about 13.0 mg / ml, about 14.0 mg / ml, about 15.0 mg / ml, about 16.0 mg / ml, about 17.0 mg / ml, about 18.0 mg / ml, about 19.0 mg / ml, about 20.0 mg / ml, about 22.0 mg / ml, about 24.0 mg / ml, about 26.0 mg / ml, about 28.0 mg / ml, about 30.0 mg / ml, about 35.0 mg / ml, about 40.0 mg / ml, about 45.0 mg / ml, or about 50.0 mg / ml, or (b) at most about 250.0 mg / ml, about 225.0 mg / ml, about 200.0mg / ml, about 175 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 75 mg / ml, about 50 mg / ml, about 45.0 mg / ml, about 40.0 mg / ml, about 35.0 mg / ml, about 30.0 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, about 1 mg / ml, about 0.5 mg / ml, or about 0.1 mg / ml. In some embodiments, the nMPC exosomes comprise a final protein concentration of at least about 1.0 mg / ml±0.5. In other embodiments, the nMPC exosomes comprise a final protein concentration of at least about 4.0 mg / ml±1.0. In some embodiments, the nMPC exosomes comprise a final protein concentration of at least about 8.0 mg / ml±2.0. In certain embodiments, the nMPC exosomes comprise a final protein concentration of at least about 16.0 mg / ml±3.0. Alternatively, or in addition, in certain embodiments, the nMPC secretome and / or the nMPC exosomes are positive for protein expression of one or more of the proteins in Table 7.

[0014] In one aspect, the composition comprises an nMPC Total Secretome comprising the nMPC secretome and the nMPC exosomes. In another aspect, the subject is administered a composition comprising the nMPC Total Secretome comprising the nMPC secretome and the nMPC exosomes. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of from about 0.10 mg / ml to about 50.0 mg / ml, or from about 0.50 mg / ml to about 20.0 mg / ml. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of (a) at least about 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, about 2.0 mg / ml, about 3.0 mg / ml, about 4.0 mg / ml, about 5.0 mg / ml, about 6.0 mg / ml, about 7.0 mg / ml, about 8.0 mg / ml, about 9.0 mg / ml, about 10.0 mg / ml, about 11.0 mg / ml, about 12.0 mg / ml, about 13.0 mg / ml, about 14.0 mg / ml, about 15.0 mg / ml, about 16.0 mg / ml, about 17.0 mg / ml, about 18.0 mg / ml, about 19.0 mg / ml, about 20.0 mg / ml, about 22.0 mg / ml, about 24.0 mg / ml, about 26.0 mg / ml, about 28.0 mg / ml, about 30.0 mg / ml, about 35.0 mg / ml, about 40.0 mg / ml, about 45.0 mg / ml, or about 50.0 mg / ml, or(b) at most about 250.0WSGR Ref. No.: 64320-710.601mg / ml, about 225.0 mg / ml, about 200.0 mg / ml, about 175 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 75 mg / ml, about 50 mg / ml, about 45.0 mg / ml, about 40.0 mg / ml, about 35.0 mg / ml, about 30.0 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, about 1 mg / ml, about 0.5 mg / ml, or about 0.1 mg / ml. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of at least about 1.0 mg / ml±0.5. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of at least about 4.0 mg / ml±1.0. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of at least about 8.0 mg / ml±2.0. In some embodiments, the nMPC secretome and the nMPC exosomes collectively comprise a final protein concentration of at least about 16.0 mg / ml±3.0. In some embodiments, the composition is acellular.

[0015] In some embodiments, any such compositions described herein are cryopreserved. In some embodiments, any such compositions described herein are lyophilized. In certain embodiments, the lyophilized composition is reconstituted in a diluent. In certain embodiments, the diluent comprises a pharmaceutically acceptable diluent. In other embodiments, the lyophilized composition is incubated for an amount of time and / or at a suitable temperature for reconstitution.

[0016] In one aspect, a symptom of a dystrophinopathy is improved following treatment compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, an nMPC secretome, or nMPC exosomes. In some embodiments, the symptom is improved (e.g., decreased) by about 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretomes, or nMPC exosomes. In other embodiments, the symptom is improved (e.g., decreased) by about 1.1 -fold, 1.5 -fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretomes, or nMPC exosomes.

[0017] In one aspect, cardiomyopathy associated with a dystrophinopathy is improved following treatment compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, an nMPC secretome, or nMPC exosomes. In some embodiments, the cardiomyopathy is improved (e.g, decreased) by about 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretomes, or nMPC exosomes. In other embodiments, the cardiomyopathy is improved (e.g., decreased) by about 1.1-fold, 1.5-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, nMPC secretomes, or nMPC exosomes. In some embodiments, the cardiomyopathy is dilated cardiomyopathy (DCM).

[0018] In some embodiments, a symptom of a dystrophinopathy is improved following treatment with the nMPC secretome compared to treatment with a placebo or compared to the subject prior to administration of the nMPC secretome. In some embodiments, the one or more symptoms is improvedWSGR Ref. No.: 64320-710.601(e.g., decreased) by about 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPC secretome. In other embodiments, the one or more symptoms is improved (e.g., decreased) by about 1.1-fold, 1.5-fold, 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPC secretome.

[0019] Symptoms of dystrophinopathy to be treated include, but are not limited to, limited mobility (e.g., difficulty walking, running, jumping, etc., waddling gait, frequent falls, difficulty rising from a seated or lying position, abnormal clumsiness, etc.), muscle pain and stiffness, and / or facial weakness. Symptoms of cardiomyopathy associated with dystrophinopathy to be treated include, but are not limited to, shortness of breath (e.g, difficulty breathing, especially during physical activity), fatigue (e.g, feeling tired, even after resting), swelling (e.g, swelling in the ankles, legs, feet, abdomen, and / or neck veins, etc.), chest pain (e.g, pain occurring after physical activity and / or eating a large meal, etc.), irregular heartbeat (e.g., a rapid, pounding, or fluttering heartbeat), fainting (e.g, syncope), dizziness, coughing (e.g, while lying down), and / or difficulty sleeping. Other symptoms of dystrophinopathy to be treated include, but are not limited to, stiffness of joints, wasting or weakening of muscles (e.g, muscles in the shoulders, upper arms and calves), heart conditions (e.g, palpitations, presyncope, syncope, poor exercise tolerance, congestive heart failure, variable cardiac rhythm disturbances, bradycardia, atrial ventricular conduction defects, heart blockage, ventricular myocardial disease with failure and stroke, secondary to cardiac arrhythmia etc. ), fainting, an awkward gait, a tendency for toe walking, fixed equinus deformities of the ankles, flexion contractures of the elbows, extension contracture of the neck, tightness of the lumbar paravertebral muscles, respiratory insufficiency, muscle wasting (e.g, of biceps, triceps, clavicular head of the pectoral muscles, abdomen, ankles, tibialis anterior muscle, etc. ), restrictive lung disease, intellectual disability, epilepsy, facial weakness, delayed motor milestones, progressive limb-girdle pattern of weakness, marked muscle wasting, hyperlordosis, loss of ambulation, ptosis, head drop, joint contractures, cardiomyopathy, weakness of the orbicularis oris muscle, limited facial expression, transverse smile, incomplete burying of eyelashes, forced eye closure, scapular winging, hearing loss, retinal vasculopathy (Coats disease), retinal detachment, blindness, progressive muscle wasting, atrophy of myocytes (affecting the eye and periocular muscles), extraocular muscle weakness, ptosis, disruptive eye movements dysphagia, impaired swallow efficiency, reduced pharyngeal constriction, reduced speed of hyoid movement, airway closure, oral regurgitation, nasal regurgitation, aspiration, post-swallow pharyngeal residue, esophageal retention, difficulty swallowing, weight loss, malnutrition, aspiration, facial weakness, hip weakness, shoulder weakness, change in voice quality, excessive fatigue, impaired cognitive function, extreme emaciation starvation, death, muscle weakness (distal and facial weakness of arms, hands, ankles, jaw, tongue or neck flexors), myotonia (often affecting the hands, tongue and jaw due to slow muscle relaxation), distal progressive muscle wasting, distal progressive muscle weakness, facial involvement, bulbar involvement, high palate, dysphonia, chronic pain (e.g, of the hands and feet), small fiber neuropathy, large fiber neuropathy, an increased riskWSGR Ref. No.: 64320-710.601for benign tumors, an increased risk for malignancies, and higher complications of adverse reactions to anesthesia and analgesic drugs relative to the general population, progressive cognitive decline, changes in brain white matter, fatigue, droopy eyelids, handshaking, breathing difficulties, swallowing difficulties, congenital hypotonia, delayed motor development, progressive muscle weakness, weak cry, poor feeding, weak muscle tone (hypotonia), damaged muscle fibers, atrophy of the skeletal muscles, weakness of the facial muscles, droopy eyelids (ptosis), an open mouth, joint deformities (contractures), impaired brain development, cobblestone lissencephaly, delayed development of speech and motor skills, moderate to severe intellectual disability, impaired social skills, seizures, impaired vision, eye abnormalities, progressive heart problems, swallowing difficulties, aspiration pneumonia, deterioration (atrophy) of skeletal muscles (limb-girdle muscle deterioration), late-onset distal myopathy (affecting ankles, feet or calves), respiratory insufficiency, cardiac failure, cardiac arrhythmia, skeletal muscle weakness due to impaired mitochondrial form and function, muscle rippling, myalgia, HyperCKemia, ankle contracture, calf hypertrophy, exercise intolerance, muscular cramps, fat infiltration, increased number of internal nuclei and rimmed vacuoles, cardiomyopathy, fatty replacement in semitendinosus, gastrocnemius and soleus, distal weakness, facial weakness, bulbar weakness, a pelvic lower girdle weakness, atrophy of the axial muscle and shoulder girdle, fatty replacement of fibers in pelvic and thigh muscles, cognitive impairment, decrease in a-dystroglycan glycosylation, myopia, epilepsy, cataracts, or a combination thereof.

[0020] Treatment may, in some instances, increase the subject’s quality of life compared to treatment with a placebo or compared to the subject prior to administration of nMPCs, nMPC secretomes, or nMPC exosomes. Alternatively, or in addition, treatment may increase the subject’s lifespan compared to treatment with a placebo or compared to the subject prior to administration of nMPCs, nMPC secretomes, or nMPC exosomes. In certain embodiments, treatment improves one or more of:Performance of Upper Limb (PUL) 2.0 from baseline to end of treatment, a Quality of Live Inventory Neuromuscular module score, cardiac structure, cardiac function (e.g, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), eccentricity (Ecc mid-LV), late gadolinium enhancement (LGE) full width half maximum (FWHM), a hemoglobin Ale (HbAlc) level, a creatine kinase -MB / creatine kinase level, a high sensitivity cardiac troponin T (hs-cTnT) level, a high sensitivity troponin 1 (hs-cTnl) level, a pulmonary function, etc. In certain instances, one symptom is improved following treatment. In certain instances, two symptoms are improved following treatment. In certain instances, three (3) symptoms are improved following treatment. In certain instances, four (4) symptoms are improved following treatment. In certain instances, five (5) symptoms are improved following treatment. In certain instances, six (6) or more symptoms are improved following treatment. Treatment may, in some instances, increase the subject’s quality of life compared to treatment with a placebo or compared to the subject prior to treatment. Alternatively, or in addition, treatment may increase the subject’s lifespan (e.g., quantity) compared to treatment with a placebo or compared to the subject prior to treatment. In certain embodiments, treatment results in stasis of one or more symptoms (e.g, improving less than 2% or not getting worse). In someWSGR Ref. No.: 64320-710.601embodiments, the subject exhibits an improvement in mobility (e.g., difficulty walking, running, jumping, etc., waddling gait, frequent falls, difficulty rising from a seated or lying position, abnormal clumsiness, etc.), muscle pain and stiffness, facial weakness, shortness of breath (e.g, difficulty breathing), fatigue, muscle weakness (e.g, feeling tired, even after resting), muscle twitching (e.g, twitching, cramping, or spasms in the muscles of the hands, feet, arms, shoulders, tongue, etc.), speech difficulty (e.g., slurred, nasal, or thick speech, difficulty projecting the voice, etc.), difficulty swallowing, difficulty chewing, trouble walking (e.g., tripping, falling, etc.), uncontrollable periods of loss of motor control (e.g., drooling, difficulty raising the foot, clumsiness, dropping things, paralysis, constipation, etc.), or a combination thereof, following administration of allogeneic, human, neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (conditioned medium), nMPC exosomes, or any combination thereof. In some embodiments, inflammation associated with dystrophinopathy is also associated with muscle loss and weakness. In certain embodiments, the symptom further comprises inflammation, oxidative stress, or a combination thereof. In one instance, treatment reduces inflammation by at least 2% or by at least 2-fold as compared to treatment with a placebo or compared to the subject prior to treatment. In another instance, treatment reduces oxidative stress by at least 2% or by at least 2-fold as compared to treatment with a placebo or compared to the subject prior to treatment.

[0021] In some embodiments, a dose of the nMPCs comprises from about 15 million to about 250 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 35 million to about 65 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 45 million to about 55 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 50 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 85 million to about 115 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 95 million to about 105 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 100 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 135 million to about 165 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 145 million to about 155 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 150 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 185 million to about 215 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 195 million to about 205 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 200 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 235 million to about 265 million nMPCs. In some embodiments, a dose of the nMPCs comprises from about 245 million to about 255 million nMPCs. In some embodiments, a dose of the nMPCs comprises about 250 million nMPCs. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration from about 0.5 / IO6nMPCs per kilogram of subject body weight (cells / kg or nMPCs / kg) to about 2.5 / 106nMPCs / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration from about 0.5 * 106cells / kg to about 2.5 / 106cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration from about 2.5 / IO6cells / kg to about 5 / IO6cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration from about 5x106cells / kg to aboutWSGR Ref. No.: 64320-710.6012.5 / 106cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 0.5 / 106cells / kg. In some embodiments, a dose of the nMPCs is administered to the subj ect at a concentration of about 0.625 / 106cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 0.7* 106cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 1.0x106cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 1.25 xlO6cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 1.43 / l()6cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 2.5 / l()6cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 2.85 / 106cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 3 / l()6cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 30 / l()6cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 50 / IO6cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 100 / IO6cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 5.0* 107cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 1.0x108cells / kg. In some embodiments, a dose of the nMPCs is administered to the subj ect at a concentration of about 2.0 * 108cells / kg. In some embodiments, a dose of the nMPCs is administered to the subject at a concentration of about 2.5 / 106cells / kg. In some embodiments, the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 28±3, wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 45±3, wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 54±3, wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 60±3, or wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 90±3. In one non-limiting embodiment, the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 28±3. In another non-limiting embodiment, the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 45±3.

[0022] In some embodiments, administration of any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein comprises intravenous (IV) injection, or intravenous (IV) catheter (e.g, intravenous (IV) infusion). In some embodiments, the nMPCs, an nMPC secretome, or nMPC exosomes are administered into the heart of the subject via intramyocardial transplantation. In some embodiments, the method comprises treating a subject diagnosed with a dystrophinopathy. In some embodiments, the method comprises treating a subject diagnosed with a dystrophinopathy with nMPCs, an nMPC secretome, or nMPC exosomes described herein. In some embodiments, the method comprises treating a subject diagnosed with a dystrophinopathy with an nMPC secretome described herein. In some embodiments, the method comprises treating a subject diagnosed with a dystrophinopathy by intravenous delivery of nMPCs, an nMPC secretome, or an nMPC exosome described herein. In some embodiments,WSGR Ref. No.: 64320-710.601the dystrophinopathy comprises a hereditary muscular dystrophy, an acquired muscular dystrophy, or an intermediate phenotype muscular dystrophy. In some embodiments, the dystrophinopathy comprises a Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), a limb-girdle muscular dystrophy (LGMD), a congenital muscular dystrophy, a congenital myopathy, a distal hereditary myopathy, a facioscapulohumeral muscular dystrophy (FSHD), an oculopharyngeal muscular dystrophy (OPMD), Emery-Dreifuss muscular dystrophy (EDMD), a congenital muscular dystrophy, a Congenital myopathy, a Myofibrillar myopathy, an Inclusion body myositis (IBM), a myotonic dystrophy, a metabolic myopathy, a mitochondrial myopathy, or an inflammatory myopathy. In some embodiments, the dystrophinopathy comprises Duchenne muscular dystrophy (DMD). In some embodiments, the dystrophinopathy comprises Becker muscular dystrophy (BMD). In some embodiments, the dystrophinopathy comprises X-linked cardiomyopathy, also known as DMD-associated dilated cardiomyopathy (DCM). In some embodiments, the dystrophinopathy comprises an Emery-Dreifuss muscular dystrophy. In some embodiments, the dystrophinopathy comprises a myotonic muscular dystrophy. In some embodiments, the dystrophinopathy comprises a facioscapulohumeral muscular dystrophy (FSMD). In some embodiments, the dystrophinopathy comprises a congenital muscular dystrophy. In some embodiments, the dystrophinopathy comprises a limb-girdle muscular dystrophy (LGMD). In some embodiments, the dystrophinopathy comprises an oculopharyngeal muscular dystrophy. In some embodiments, the dystrophinopathy comprises a congenital muscular dystrophy. In some embodiments, the dystrophinopathy comprises a congenital myopathy. In some embodiments, the dystrophinopathy comprises a myofibrillar myopathy. In some embodiments, the dystrophinopathy comprises an inclusion body myositis (IBM). In some embodiments, the dystrophinopathy comprises a myotonic dystrophy. In some embodiments, the dystrophinopathy comprises a metabolic myopathy. In some embodiments, the dystrophinopathy comprises a mitochondrial myopathy. In some embodiments, the dystrophinopathy comprises an inflammatory myopathy. In some embodiments, the method comprises treating a dystrophinopathy in a subject in need thereof. In some embodiments, the method comprises treating cardiomyopathy associated with a dystrophinopathy in a subject in need thereof. In some embodiments, the method comprises treating cardiomyopathy in a subject diagnosed with a dystrophinopathy. In some embodiments, the method comprises treating cardiomyopathy in a subject diagnosed with Duchenne muscular dystrophy (DMD). In some embodiments, the method comprises treating cardiomyopathy in a subject diagnosed with Becker muscular dystrophy (BMD). In some embodiments, the method comprises treating X-linked cardiomyopathy, also known as DMD-associated dilated cardiomyopathy (DCM).In some embodiments, the nMPCs are administered to the subject once every 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 days. In some embodiments, the nMPCs are administered to the subject once every 28 ±3 days, once every 45±3 days, once every 54±3 days, once every 60±3 days, once every 70±3 days, once every 80±3 days, once every 90±3 days, or once everyWSGR Ref. No.: 64320-710.601100±3 days. In some embodiments, the nMPCs, an nMPC secretome, or an nMPC exosome are administered to the subject once every twenty-eight (28) ±3 days. In some embodiments, the nMPCs, an nMPC secretome, or an nMPC exosome are administered to the subject once every 29, 30, 31, 32, 33, 34, 35, or 36 ±3 days. In some embodiments, the nMPCs, an nMPC secretome, or an nMPC exosome are administered to the subject for from about 1 month to about 100 years. In some embodiments, the nMPCs, an nMPC secretome, or an nMPC exosome are administered to the subject for from about 1 month to about 10 years, or from about 1 year to about 50 years. In one embodiment, a dose of the nMPCs, nMPC secretome, and / or nMPC exosomes is administered to the subject about every twentyeight (28) ±3 days or about every thirty (30) ±3 days. In some embodiments, the subject is administered a first dose of the nMPCs, nMPC secretome, and / or nMPC exosomes at day 0 and a second dose of the nMPCs at day 28 ±3. In some embodiments, the subject is assessed at day 7 following treatment or about every 7 days following treatment.

[0023] In some embodiments, the method further comprises administering to the subject one or more additional therapeutic agent(s). In some embodiments, the one or more additional therapeutic agent(s) help manage some symptoms of dystrophinopathy. In some embodiments, the one or more additional therapeutic agent(s) help manage some symptoms of cardiomyopathy associated with dystrophinopathy. In some embodiments, the method further comprises administering the nMPCs, nMPC secretome (e.g, secretomes, exosomes, peptides, proteins, nucleic acids, etc.), and / or nMPC exosomes concomitantly with other standard of care treatment. In some embodiments, the method further comprises administering the nMPCs, nMPC secretome, and / or nMPC exosomes concomitantly with other standard of care treatment (e.g, physical, occupational, speech, respiratory, nutritional therapies, corticosteroid medication (e.g., prednisone or deflazacort), regular cardiac and respiratory monitoring, and supportive care mechanical ventilation, etc.).

[0024] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject to be treated is from about birth to about 1 year of age, 1 year to about 4 years of age, 4 years of age to about 30 years of age, from about 4 years of age to about 18 years of age, from about 18 years of age to about 30 years of age, from about 5 years to about 14 years of age, from about 15 years to about 40 years of age, from about 1 to about 10 years of age, from about 11 to about 20 years of age, from about 21 to about 30 years of age, from about 31 to about 40 years of age, from about 51 to about 60 years of age, from about 71 to about 80 years of age, from about 81 to about 90 years of age, or about 91+ years of age. In some embodiments, the mammal is a human. In certain embodiments, the subject to be treated is from birth to 18 years of age. In certain embodiments, the subject to be treated is from about 4 to about 18 years of age. In certain embodiments, the subject to be treated is from about 4 to about 30 years of age. In certain embodiments, the subject to be treated is from about 18 to about 30 years of age. In certain embodiments, the subject to be treated is from about 19 to about 25 years of age. In certain embodiments, the subject to be treated is 26 years of age or older. In some embodiments, the subject exhibits an improved quality of life following treatment as compared to a placebo or compared to the subject prior to treatment.WSGR Ref. No.: 64320-710.601

[0025] In any of such embodiments, the subject being treated is partially or completely treated. In any of such embodiments, a symptom of the subject being treated is partially or completely treated. Treatment can be assessed compared to a placebo or compared to the subject prior to administration of a composition described herein. Efficacy of treatment can also be assessed compared to a healthy patient population. In certain embodiments, cardiomyopathy of a subject diagnosed with a dystrophinopathy is partially or completely treated.

[0026] In any of such methods, the subject to be treated can be a mammal such as, for example, a human. In another embodiment, the composition is administered intravenously for between about 30 to about 60 minutes, about 45 to about 60 minutes, about 45 to about 75 minutes, about 60 minutes to about 90 minutes, about 60 minutes to about 120 minutes, about 60 minutes to about 180 minutes, about 90 minutes to about 120 minutes, or about 90 minutes to about 180 minutes. In some embodiments, the nMPCs are infused via IV catheter for from about 35 minutes to about 180 minutes, from about 40 minutes to about 90 minutes, from about 55 minutes to about 65 minutes, or about 60 minutes. In some embodiments, a composition as described herein can be infused via IV catheter for at least about 30 minutes to about 90 minutes, or at least about 60 minutes to about 180 minutes. In some embodiments, the subject is screened one or more times prior to treatment, during treatment, and / or after treatment. In some embodiments, the screening comprises a physical evaluation, medical history review, and one or more diagnostic tests. In certain embodiments, the one or more diagnostic tests comprise(s) genetic testing (e.g., DMD gene deletion-duplication analysis, Sanger DNA sequencing, Next-generation DNA sequencing, RNA sequencing, etc.), immunohistochemical analyses (e.g, analysis of muscle biopsy cryosections, immunoblots), biochemical analyses (e.g, protein truncation tests, PCR, etc.), and / or blood tests (e.g, detection of elevated Creatine Kinase (CK) levels, etc.).1. In some embodiments, one or more proinflammatory cytokines in the subject are reduced by at least 2% compared to treatment with a placebo or compared to the subject prior to treatment. In certain embodiments, the one or more proinflammatory cytokines comprise IL-1, IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, TNF-a, IFN-y, or a combination thereof. In one embodiment, the one or more proinflammatory cytokines comprise IL-10, IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, TNF-a, and IFN-y. In another embodiment, the one or more proinflammatory cytokines comprise IL -8, IL- 17a, MCP-1, TNF-a, and IFN-y. In yet another embodiment, the one or more proinflammatory cytokines comprise IL-8, MCP-1, and TNF-a. In one embodiment, the one or more proinflammatory cytokines comprise IL-17a and IFN-y. In some embodiments, the administration of the allogeneic, human, neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (conditioned medium), nMPC exosomes, or any combination thereof, inhibits IL-10, IL-6, IL-8, IL-12, IL-17a, IL-18, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-a, interferon gamma (IFN-y), or a combination thereof by at least 2% or by at least 2-fold as compared to treatment with a placebo or compared to the subject prior to treatment. In some embodiments, the one or more proinflammatory cytokines comprise IL-8, IL-17A, MCP-1, or a combination thereof. In some embodiments, one or more anti-inflammatory cytokines in the subject are increased by at least 2% compared to treatment with a placebo or compared to theWSGR Ref. No.: 64320-710.601subject prior to treatment. In some embodiments, the one or more anti-inflammatory cytokines comprise IL-10. In some embodiments, the one or more proinflammatory cytokines comprise IL-8, IL-17A, MCP-1, or a combination thereof. In some embodiments, one or more anti-inflammatory cytokines in the subject are increased by at least 2% compared to treatment with a placebo or compared to the subject prior to treatment. In some embodiments, the one or more anti-inflammatory cytokines comprise IL-10. In some embodiments, the administration of the allogeneic, human, neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (conditioned medium), nMPC exosomes, or any combination thereof, reduces levels of IL-8, IL-17A, and MCP-1, and increases levels of IL-10.

[0027] In some embodiments, the subject has an improved quality of life following treatment compared to treatment with a placebo or compared to the subject prior to treatment. In some embodiments, the subject is biologically a male. In some embodiments, the subject is biologically a female.

[0028] In some embodiments, motor neuron function improves by at least 2% following treatment compared to a placebo or compared to the subject prior to treatment. In some embodiments, muscle loss is inhibited or slowed at least 2% following treatment compared to a placebo or compared to the subject prior to treatment. In some embodiments, muscle weakness is inhibited or slowed at least 2% following treatment compared to a placebo or compared to the subj ect prior to treatment. In some embodiments, the administration of the nMPCs results in muscle regeneration, increased muscle strength, increased flexibility, increased range of motion, increased stamina, reduced fatigability, increased blood flow, improved cognition, improved pulmonary function, inflammation inhibition, reduced muscle fibrosis, and / or reduced muscle necrosis. In some embodiments, muscle wasting, muscle weakness, muscle fragility, muscle necrosis, muscle fibrosis, joint contracture, skeletal deformation, cardiomyopathy, impaired swallowing, impaired bowel and bladder function, muscle ischemia, cognitive impairment, behavioral dysfunction, socialization impairment, scoliosis, and / or impaired respiratory function are improved by at least 2% following treatment compared to a placebo or compared to the subject prior to treatment. In each of the foregoing, improvement may be by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to a placebo or compared to the subject prior to treatment.

[0029] In some embodiments, the method further comprises administering to the subject one or more additional therapeutic agent(s). In some embodiments, the one or more additional therapeutic agent(s) comprise(s) an aldosterone antagonist, an angiotensin-converting enzyme inhibitor (ACEi), an angiotensin receptor blocker (ARB), a beta blocker, a blood thinner, a cardiac glycoside, a diuretic, a biguanide, a statin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a glucagon- 1 receptor agonist, a corticosteroid, an exon-skipping therapy, an AAV-based gene therapy, a HD AC inhibitor, or a combination thereof.

[0030] In some embodiments, the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising DMD. In some embodiments, the mutation is in a gene encoding dystrophin. In some embodiments, the gene is in aXp21.2 chromosome. In some embodiments, the mutation is an out-of-frame mutation of a dystrophin gene open reading frame, and the out-of-frameWSGR Ref. No.: 64320-710.601mutation causes alack of dystrophin expression. In some embodiments, the nMPCs comprise a wild-type dystrophin gene encoding a functional dystrophin protein.

[0031] In some embodiments, the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising Becker muscular dystrophy. In some embodiments, the mutation is in a gene encoding dystrophin. In some embodiments, the gene is in a Xp21.2 chromosome. In some embodiments, the mutation is an in-frame mutation, and the in-frame mutation causes dystrophin deficiency or dysfunction. In some embodiments, the nMPCs comprise a wild-type dystrophin gene encoding a functional dystrophin protein.

[0032] In some embodiments, the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising X-linked cardiomyopathy (or DMD-associated dilated cardiomyopathy (DCM)). In some embodiments, the mutation is in a gene encoding dystrophin. In some embodiments, the gene is in a Xp21.2 chromosome. In some embodiments, the mutation is an in-frame mutation, and the in-frame mutation causes dystrophin deficiency or dysfunction. In some embodiments, the nMPCs comprise a wild-type dystrophin gene encoding a functional dystrophin protein.

[0033] In any of such methods, the nMPCs are stable in storage at a temperature for a period of time. In some embodiments, the temperature is about 4 °C, 1 °C, 0 °C, -10 °C, -20 °C, or -80 °C. In some embodiments, the period of time is at least about 1, 2, 3, 4, 5, 6, or 7 days; at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22,23, 24,25, 26, 27,28, 29, 30,31, 32,33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks; or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months. In some embodiments, the nMPCs are stored in cell cryopreservation media-CS10 (CRYOSTOR®; Sigma- Aldrich, Israel). In some embodiments, the nMPCs are thawed in a 37 °C water bath until a single ice crystal remained prior to administration to the subject. In some embodiments, the nMPCs are further washed with a volume of Complete Medium (CM). In some embodiments, the nMPCs are washed twice with a volume of Complete Medium (CM). In some embodiments, the volume is at least about 10 ml.INCORPORATION BY REFERENCE

[0034] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Various features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained byWSGR Ref. No.: 64320-710.601reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0036] FIGS. 1A-1G are data showing improvements in various aspects of cardiac symptoms associated with dystrophinopathies after intravenous administration of 100 x 106nMPCs at Day 0 (first dose) and Day 28 (second dose), and assessed at Day 0 (baseline) and Day 56 (end of study). Line charts show Stroke Volume Index (SVI) data (FIG. 1A), walking distance from a 6-Minute Walk Test (6MWT) (FIG. IB), scores from a Kansas City Cardiomyopathy Questionnaire (KCCQ) (FIG. 1C), data for Left Ventricular Filling Pressure or a Diastolic Dysfunction (E / e’ mean) (FIG. ID), data for N-terminal pro-B-type natriuretic peptide (NT-proBNP) (FIG. IE), data for mean end-diastolic volume index (EDVI) (FIG. IF), and data for Estimated Glomerular Filtration Rate (eGFR) (FIG. 1G).

[0037] FIG. 2 is a schematic illustrating the study scheme. Part 1 comprises 120 participants (1:1 nMPCs vs. placebo); and Part 2 comprises up to 120 participants (nMPCs).

[0038] FIGS. 3A-3D are data showing the effect of nMPC secretome on inflammation in DMD skeletal myocytes by assessing myocyte expression levels of exemplary inflammatory markers: interleukin (IL)-8 (IL-8) (FIG. 3A), IL-17A(FIG.3B), monocyte chemoattractant protein- 1 (MCP-1) (FIG. 3C), and IL-10 (FIG. 3D). iPSC-derived DMD skeletal myocytes were treated with lipopolysaccharides (LPS) (1 pg / ml) in the presence or absence of nMPC secretome for 24 hours (left portion of each subfigure) or 48 hours (right portion of each subfigure). Cytokine analyses were performed on each condition’s cell culture supernatant using electrochemiluminescence (MESO SCALE DISCOVERY®). The left (24-hour) and right (48-hour) panels of each bar chart shows a marker’s levels after LPS -stimulated DMD skeletal myocytes were divided into the following conditions: (1) first bar - control group (cells only, with neither LPS nor nMPC secretome); (2) second bar - LPS-treated group (cells stimulated with 1 pg / ml LPS only, no nMPC secretome); (3) third bar - first treatment group in which cells were incubated with 1 mg / ml LPS and 0.8 pg / ml nMPC secretome; and (4) fourth bar - second treatment group in which cells were incubated with 1 mg / ml LPS and 4 pg / ml nMPC secretome. Data are presented as mean ± SEM and analyzed by one-way ANOVA followed by Tukey’s post hoc test. *p<0.05, **p<0.01, ****p<0.001.DETAILED DESCRIPTION

[0039] The details of one or more inventive embodiments are set forth in the accompanying drawings, the claims, and the description herein. Other features, objects, and advantages of the inventive embodiments disclosed and contemplated herein can be combined with any other embodiment unless explicitly excluded. It is to be understood that the embodiments of the disclosures herein are illustrative of the principles of the present disclosure. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto. Any combination of the abovedescribed elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context. Other modifications that may be employed are within the scope of the disclosure. Thus, by way of example, but not of limitation, alternativeWSGR Ref. No.: 64320-710.601configurations of the present disclosure may be utilized in accordance with the teachings herein.Accordingly, the present disclosure is not limited to that precisely as shown and described.

[0040] The present disclosure provides, among other things, methods and compositions for treating cardiomyopathy in muscular dystrophy, including Duchenne muscular dystrophy (DMD), based on neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome, and / or nMPC exosomes as therapeutics. In particular embodiments, an nMPC secretome can comprise, for example, exosomes, growth factors, cytokines, macromolecules, such as peptides, proteins, and nucleic acids (e.g., miRNAs), or a combination thereof. In some embodiments, the present disclosure provides methods of treating a symptom of dystrophinopathy, including, for example, administering to an individual who is suffering from or susceptible to a dystrophinopathy an effective amount of nMPCs, an nMPC secretome, or nMPC exosomes such that at least one symptom or feature of dystrophinopathy is reduced by at least 2% or by at least 2-fold in intensity, severity, or frequency, or has delayed onset compared to treatment with a placebo. In some instances, a symptom of dystrophinopathy comprises cardiomyopathy associated with dystrophinopathy. In certain instances, a dystrophinopathy comprises DMD, BMD, X-linked cardiomyopathy, a limb-girdle muscular dystrophy (LGMD), a congenital muscular dystrophy, a congenital myopathy, a distal hereditary myopathy, a facioscapulohumeral muscular dystrophy (FSHD), an oculopharyngeal muscular dystrophy (OPMD), Emery -Dreifuss muscular dystrophy (EDMD), a congenital muscular dystrophy, a Congenital myopathy, a Myofibrillar myopathy, an Inclusion body myositis (IBM), a myotonic dystrophy, a metabolic myopathy, a mitochondrial myopathy, or an inflammatory myopathy.Dystrophinopathy

[0041] Dystrophin is a cytoplasmic protein encoded by the DMD gene and links cytoskeletal actin filaments to membrane proteins. Dystrophin protein is mostly localized in skeletal and cardiac muscles, with smaller amounts expressed in the brain. Under normal conditions, dystrophin acts as a shock absorber during muscle fiber contraction by linking the actin of the contractile apparatus to the layer of connective tissue surrounding each muscle fiber. In muscle, dystrophin is localized at the cytoplasmic face of the sarcolemma membrane.

[0042] The DMD gene is approximately 2.5 Mb in length, located on the X chromosome at position Xp21. The dystrophin gene contains 79 exons that are processed into an 11,000 base pair mRNA that is translated into a 427 kilodalton (kDa) protein. The sequence for an exemplary, full-length, wild-type DMD gene encoding a functional dystrophin protein can be found in SEQ ID NO: 1. Full-length dystrophin is a large (427 kDa) protein comprising a number of subdomains that collectively confer its function. The sequence for an exemplary, full-length, wild-type dystrophin polypeptide or protein can be found in SEQ ID NO: 2. Such exemplary sequences can be found in Table 1.

[0043] Functionally, dystrophin acts as a linker between the actin filaments and the extracellular matrix within muscle fibers. The N-terminus of dystrophin is an actin-binding domain, while the C-terminus interacts with a transmembrane scaffold that anchors the muscle fiber to the extracellular matrix. Upon muscle contraction, dystrophin provides structural support that allows the muscle tissue to withstandWSGR Ref. No.: 64320-710.601mechanical force. Common mutations that cause Duchenne Muscular Dystrophy (DMD) or Becker Muscular Dystrophy (BMD) comprise large deletion mutations of one or more exons (between about 60% and about 70%), but duplication mutations (between about 5% and about 10%), and single nucleotide variants (e.g, small deletions or insertions, single-base changes, and splice site changes that contribute to approximately 25%-35%of pathogenic variants in males with DMD, and about 10%-20% of males with BMD) can also cause pathogenic dystrophin variants. In DMD, mutations often lead to a frame shift resulting in a premature stop codon and a truncated, non-functional or unstable protein. Nonsense point mutations can also result in premature termination codons that cause similar frame shifts. While mutations causing DMD can affect any exon, exons 2-20 and 45-55 are frequent sites for large deletion and duplication mutations. In-frame deletions result in the less severe Becker muscular dystrophy (BMD), in which patients express a truncated, partially functional dystrophin.Table 1. Exemplary Dystrophin SequencesIdentity SequenceExemplary > NM_004006.3 Homo sapiens dystrophin (DMD), transcript human, full- variant Dp 427m, mRNA ATCAGTTACTGTGTTGACTCACTCAGTGTTGGGATCACTCACTTTCCCCCTACAGGACT length, wildCAGATCTGGGAGGCAATTACCTTCGGAGAAAAACGAATAGGAAAAACTGAAGTGTTACT type DMD gene, T T TT TT AAAGCT GCTGAAGT TT GT TGGT TT CT GATT GT TT TT AAGC CT AC TGGAGCAAT AAAGTT TGAAGAACTTTTACCAGGTT TT TT TT AT CGCTGCCTTGAT AT ACACTT TT CAA transcript AATGCT TT GGTGGGAAGAAGTAGAGGACTGTT AT GAAAGAGAAGAT GTTCAAAAGAAAA CATT CACAAAAT GGGT AAAT GC ACAATT TT CT AAGT TT GGGAAGCAGC AT AT TGAGAAC variant Dp427m CTCTTCAGTGACCTACAGGATGGGAGGCGCCTCCTAGACCTCCTCGAAGGCCTGACAGG (SEQ ID NO: GCAAAAAC TGCCAAAAGAAAAAGGAT CC ACAAGAGT TCAT GCCCTGAACAAT GT CAAC A AGGCACTGCGGGTTTTGCAGAACAATAATGTTGATTTAGTGAATATTGGAAGTACTGAC1) AT CGTAGATGGAAATCAT AAAC TGAC TC TT GGTT TGAT TT GGAATATAAT CC TC CACT G GC AGGT CAAAAATGTAAT GAAAAATATC AT GGCT GGAT TG CAAC AAAC CAAC AGTGAAA AGATTCTCCTGAGCTGGGTCCGACAATCAACTCGTAATTATCCACAGGTTAATGTAATC AACTTCACCACCAGCTGGTCTGATGGCCTGGCTTTGAATGCTCTCATCCATAGTCATAG GCCAGACCTATTTGACTGGAATAGTGTGGTTTGCCAGCAGTCAGCCACACAACGACTGG AACATGCATT CAACAT CGCCAGAT AT CAAT TAGGCATAGAGAAACT AC TC GATC CT GAA GATGTT GATACCACCTATCCAGATAAGAAGTCCATCTTAATGTACATCACAT CACT CT T CCAAGT TT TGCCTCAACAAGTGAGCATT GAAGCCATCCAGGAAGTGGAAATGTT GCCAA GGCC AC CT AAAGTGACTAAAGAAGAACATT TT CAGT TACATC AT CAAATGCACT AT TC T CAAC AGAT CACGGT CAGT CT AGCACAGGGATATGAGAGAACT TCTT CC CC TAAGCC TC G ATTCAAGAGCTATGCCTACACACAGGCTGCTTATGTCACCACCTCTGACCCTACACGGA GC CC AT TT CC TT CACAGCAT TT GGAAGC TC CT GAAGACAAGT CATT TGGC AGTT CATT G AT GGAGAGTGAAGT AAACCT GGAC CGTT AT CAAACAGCTT T AGAAGAAGT AT TATC GT G GC TT CT TT CT GCTGAGGACACATT GCAAGC ACAAGGAGAGAT TT CT AATGAT GT GGAAG T GGT GAAAGACCAGTT TCAT AC TC AT GAGGGGTACATGAT GGAT TT GACAGC CC AT CAG GGCC GGGT TGGT AATATTCTACAATTGGGAAGTAAGCTGATTGGAACAGGAAAATTATC AGAAGATGAAGAAACTGAAGTACAAGAGCAGATGAATCTCCTAAATTCAAGATGGGAAT GC CT CAGGGT AGCT AGCATGGAAAAACAAAGCAATT TACATAGAGT TT TAAT GGAT CT C CAGAAT CAGAAACT GAAAGAGT TGAATGAC TGGC TAACAAAAACAGAAGAAAGAACAAG GAAAAT GGAGGAAGAGCCTCTT GGACCT GATCTT GAAGACCTAAAACGCCAAGT ACAAC AACATAAGGT GCTT CAAGAAGATC TAGAACAAGAACAAGT CAGGGT CAAT TC TC TC AC T CACATGGT GGTGGT AGTT GATG AATC TAGT GGAGAT CACGCAAC TGCT GC TT TGGAAGA ACAACT TAAGGT AT TGGGAGAT CGAT GGGCAAAC AT CT GT AGAT GGAC AGAAGACC GC T GGGT TC TT TT ACAAGACATCCT TC TCAAAT GG CAAC GT CT TACT GAAGAACAGT GC CT T T T TAGT GC AT GGCT TT CAGAAAAAGAAGAT GC AGTGAACAAGAT TC AC ACAACT GGCT T T AAAGATCAAAATGAAAT GT TATCAAGT CT TCAAAAACTGGC CGTT TT AAAAGC GGAT C T AGAAAAGAAAAAGCAAT CCAT GGGCAAAC TGTATT CACT CAAACAAGAT CT TC TT TC A AC AC TGAAGAAT AAGT CAGT GACC CAGAAGAC GGAAGCAT GGCT GGAT AACT TT GC CC G GT GT TGGGAT AATT TAGT GCAAAAAC TT GAAAAGAGTACAGCACAGAT TT CA CAGGGT GT C AC CACC AC TCAGCCAT CACT AACA GAGA CAAC TGTAAT GGAAAC AGTAAC TA GGGT GWSGR Ref. No.: 64320-710.601Identity SequenceAC CACAAGGGAACAGATCCT GGTAAAGC AT GC TCAAGAGGAACT TC CACC AC CACC TC C CCAAAAGAAGAGGCAGAT TACT GT GGAT TC TGAAAT TAGGAAAAGGTT GGAT GT TGAT A TAACTGAACTTCACAGCTGGATTACTCGCTCAGAAGCTGTGTTGCAGAGTCCTGAATTT GCAATC TT TC GGAAGGAAGGCAAC TT CT CAGACT TAAAAGAAAAAGTCAATGCC AT AGA GCGAGAAAAAGCTGAGAAGTTCAGAAAACTGCAAGATGCCAGCAGATCAGCTCAGGCCC T GGT GGAACAGATGGT GAAT GAGGGT GT TAAT GC AGAT AGCATCAAACAAGC CT CAGAA CAAC TGAACAGCCGGT GGAT CGAATT CT GC CAGT TGCT AAGT GAGAGACT TAAC TGGC T GGAGTATC AGAACAACAT CATC GC TT TC TA TAAT CAGCTACAACAATT GGAGCAGATGA CAAC TACT GC TGAAAACT GGTT GAAAAT CCAACC CACCAC CCCATC AGAGCCAACAGC A AT TAAAAGTC AGTT AAAAAT TT GT AA GGAT GAAGTCAACCGGCT AT CAGATC TT CAAC C T CAAAT TGAACGAT TAAAAATT CAAAGC AT AGCC CT GAAAGAGAAAGGACAAGGAC CCA T GTT CC TGGATGCAGACT TT GT GGCC TT TACAAATCAT TT TAAGCAAGTC TT TT CT GAT GT GC AGGC CAGAGAGAAAGAGC TACAGACAAT TT TT GACACT TT GC CACCAATGCGCT A TCAGGAGACCATGAGTGCCATCAGGACATGGGTCCAGCAGTCAGAAACCAAACTCTCCA TACCTCAACT TAGTGTCACCGACT AT GAAATCAT GGAGCAGAGACT CGGGGAAT TGCAG GCTTTACAAAGTTCTCTGCAAGAGCAACAAAGTGGCCTATACTATCTCAGCACCACTGT GAAAGAGATGTCGAAGAAAGCGCCCT CT GAAATT AGCCGGAAATAT CAAT CAGAAT TT G AAGAAATT GA GGGACGCT GGAAGAAGCT CT CC TC CCAGCT GGTT GAGCAT TGTCAAAAG CT AGAGGAGCAAAT GAAT AAAC TC CGAAAAAT TC AGAATCACAT ACAAAC CC TGAAGAA AT GGAT GGCT GAAGTTGATGTT TT TCTGAAGGAGGAATGGCCTGCCCT TGGGGATT CAG AAAT TC TAAAAAAGCAGCTGAAAC AGTGCAGACT TT TAGT CAGT GATATT CA GA CAAT T C AGC CC AG TC TAAACAGT GT CAAT GAAG GT GG GC AGAAGAT AAAGAAT GAAG CAGAGC C AGAGTT TGCT TCGAGACTTGAGACAGAACT CAAAGAACTTAACACT CAGT GGGATCACA TGTGCCAACAGGTCTATGCCAGAAAGGAGGCCTTGAAGGGAGGTTTGGAGAAAACTGTA AGCC TC CAGAAAGATCTATCAGAGAT GC AC GAAT GGAT GACACAAGCT GAAGAAGAGT A T C TT GA GA GA GATT TT GAAT AT AAAA CT CC AGAT GAAT TACAGAAAGC AGTT GAAGAGA TGAAGAGAGCTAAAGAAGAGGCCCAACAAAAAGAAGCGAAAGTGAAACTCCTTACTGAG T C TGTAAATAGT GT CATAGCTCAAGC TC CACC TGTAGCACAAGAGGCC TT AAAAAAGGA ACTTGAAACTCTAACCACCAACTACCAGTGGCTCTGCACTAGGCTGAATGGGAAATGCA AGAC TT TGGAAGAAGT TT GGGC AT GT TGGC AT GAGT TATT GT CATACT TGGAGAAAGC A AACAAGTGGC TAAATGAAGT AG AATT TAAACT TAAAAC CACT GAAAAC AT TCCT GGCGG AG CT GA GG AAAT CT CT GAGGTG CT AG AT TC AC TT GAAAAT TT GATG CG AC AT TC AG AG G ATAACCCAAATCAGATTCGCATATTGGCACAGACCCTAACAGATGGCGGAGTCATGGAT GAGC TAAT CAAT GAGGAACT TGAGAC AT TT AATT CT CGTT GGAGGGAACT AC AT GAAGA GGCTGTAAGGAGGCAAAAGTTGCTTGAACAGAGCATCCAGTCTGCCCAGGAGACTGAAA AATC CT TACACT TAAT CCAGGAGT CC CT CACATT CATT GACAAGCAGT TGGC AGCT TAT ATTGCAGACAAGGTGGACGCAGCTCAAATGCCTCAGGAAGCCCAGAAAATCCAATCTGA T T TGACAAGT CATGAGAT CAGT TT AGAAGAAATGAAGAAACATAAT CAGGGGAAGGAGG CT GC CCAAAGAGTCCT GT CT CAGATT GATGTT GC ACAGAAAAAATT ACAAGATGTC TC C AT GAAGTT TC GATT AT TCCAGAAACCAGCCAATT TT GAGCAGCGTCTACAAGAAAGTAA GATGAT TT TAGATGAAGT GAAGAT GC AC TT GC CT GCAT TGGAAACAAAGAGT GT GGAAC AGGAAGTAGT ACAGTCACAGCTAAAT CATT GT GT GAACTTGTATAAAAGT CT GAGT GAA GT GAAGTC TGAAGT GGAAAT GGTGAT AAAGAC TGGACGTCAGAT TGTACAGAAAAAGC A GACGGAAAAT CCCAAAGAACTT GATGAAAGAGTAACAGCT TT GAAATT GCATTATAATG AGCTGGGAGCAAAGGTAACAGAAAGAAAGCAACAGTTGGAGAAATGCTTGAAATTGTCC CGTAAGAT GCGAAAGGAAATGAAT GT CT TGACAGAATGGCTGGCAGCT ACAGAT AT GGA AT TGACAAAGAGAT CAGCAGTT GAAG GAAT GC CT AG TAAT TT GGAT TC TGAAGT TGCC T GGGGAAAGGCTACTCAAAAAGAGATTGAGAAACAGAAGGTGCACCTGAAGAGTATCACA GAGGTAGGAGAGGCCTTGAAAACAGT TT TGGGCAAGAAGGAGACGT TGGT GGAAGATAA ACTCAGTCTTCTGAATAGTAACTGGATAGCTGTCACCTCCCGAGCAGAAGAGTGGTTAA AT CT TT TGTT GGAATACCAGAAACACAT GGAAACTTTTGACCAGAATGTGGACCACAT C ACAAAGTGGATCAT TCAGGCTGAC AC AC TT TT GGAT GAAT CAGAGAAAAAGAAACC CCA GCAAAAAGAAGACGTGCTTAAGCGTTTAAAGGCAGAACTGAATGACATACGCCCAAAGG TGGACT CT ACACGTGACCAAGCAGCAAACT TGAT GGCAAACCGCGGTGACCACT GCAGG AAAT TAGT AGAGCCCCAAAT CT CAGAGC TCAACC AT CGAT TT GCAGCC AT TT CACACAG AATT AA GA CT GGAAAGGCCT CC AT TC CT TT GAAG GAAT TGGAGCAGTT TAAC TC AGAT A TACAAAAATT GCTTGAACCACT GG AGGCTGAAATTCAGCAGGGGGT GAAT CT GAAAGAG GAAGAC TT CAAT AAAGAT AT GAAT GAAGACAATGAGGGTACT GT AAAA GAAT TGTT GCA AAGAGGAGACAACTTACAACAAAGAATCACAGATGAGAGAAAGCGAGAGGAAATAAAGA TAAAACAGCAGCTGTTACAGACAAAACATAATGCTCTCAAGGATTTGAGGTCTCAAAGA AGAAAAAAGGCTCTAGAAATTTCTCATCAGTGGTATCAGTACAAGAGGCAGGCTGATGAT C TC CT GAAATGCT TGGATGAC AT TGAAAAAAAATT AGCCAGCCTACC TGAGCC CAGAGWSGR Ref. No.: 64320-710.601Identity SequenceAT GAAAGGAAAATAAAGGAAAT TGAT CGGGAATT GCAGAAGAAGAAAGAGGAGCTGAAT GCAGTGCGTAGGCAAGCTGAGGGCTTGTCTGAGGATGGGGCCGCAATGGCAGTGGAGCC AACT CAGATCCAGCTCAGCAAGCGCT GGCGGGAAATTGAGAGCAAATT TGCT CAGT TT C GAAGAC TCAACT TT GCACAAAT TC AC AC TGTC CGTGAAGAAACGAT GATGGT GATGAC T GAAGAC AT GC CT TT GGAAAT TT CT TATGTGCC TT CT AC TT AT TT GACT GAAATCACTC A TGTCTCACAAGCCCTATTAGAAGTGGAACAACTTCTCAATGCTCCTGACCTCTGTGCTA AGGACTTTGAAGATCTCTTTAAGCAAGAGGAGTCTCTGAAGAATATAAAAGATAGTCTA CAACAAAGCT CAGGTCGGATTGACAT TATT CATAGCAAGAAGACAGCAGCAT TGCAAAG TGCAACGCCTGTGGAAAGGGTGAAGCTACAGGAAGCTCTCTCCCAGCTTGATTTCCAAT GGGAAAAAGTTAACAAAATGTACAAGGACCGACAAGGGCGATTTGACAGATCTGTTGAG AAAT GGCGGC GT TT TCAT TATGAT AT AAAGAT AT TT AATCAGTGGC TAAC AGAAGC TGA AC AGTT TC TC AGAAAGACACAAAT TC CT GAGAAT TGGGAACATGCT AAAT ACAAAT GGT AT CT TAAGGAACTCCAGGATGGCATT GGGCAGCGGCAAACTGTTGT CAGAACAT TGAAT GCAACT GGGGAAGAAATAAT TC AGCAAT CC TCAAAAACAGAT GC CAGT AT TC TACAGGA AAAATT GGGAAGCCTGAATCTGCGGT GGCAGGAGGTCTGCAAACAGCT GT CAGACAGAA AAAAGAGGCT AGAAGAACAAAAGAAT AT CT TGTCAGAATTTCAAAGAGAT TTAAAT GAA T T TGTT TT AT GGTT GGAGGAAGCAGATAAC AT TGCT AGTATCCCAC TT GAAC CT GGAAA AGAGCAGCAACTAAAAGAAAAGCTTGAGCAAGTCAAGTTACTGGTGGAAGAGTTGCCCC TGCGCCAGGGAATTCTCAAACAATTAAATGAAACTGGAGGACCCGTGCTTGTAAGTGCT CC CATAAGCC CAGAAGAGCAAGAT AAAC TT GAAAAT AAGCTCAAGC AGACAAAT CT CCA GT GGAT AAAGGT TT CCAGAGCT TT AC CT GAGAAACAAGGAGAAATT GAAGCT CAAATAA AAGACC TT GGGCAGCT TGAAAAAAAGCT TGAAGACCTT GAAGAGCAGT TAAATC AT CT G CTGCTGTGGTTATCTCCTATTAGGAATCAGTTGGAAATTTATAACCAACCAAACCAAGA AGGACCATTTGACGTTAAGGAAACTGAAATAGCAGTTCAAGCTAAACAACCGGATGTGG AAGAGATT TT GT CT AAAGGGCAGC AT TT GT ACAAGGAAAAACCAGC CACT CAGC CAGT G AAGAGGAAGT TAGAAGAT CT GAGC TC TGAGTGGAAGGCGGTAAACC GT TT AC TT CAAGA GCTGAGGGCAAAGCAGCCTGACCTAGCTCCTGGACTGACCACTATTGGAGCCTCTCCTA CT CA GA CT GT TACT CT GGTGAC ACAACC TGTGGT TACT AAGGAAAC TGCC AT CT CCAAA CTAGAAATGCCATCTTCCTTGATGTTGGAGGTACCTGCTCTGGCAGATTTCAACCGGGC T T GGAC AGAACT TACCGACT GGCT TT CT CT GC TT GATCAAGT TATAAAAT CACAGAGGG T GAT GG TG GG TGAC CT TGAGGA TATC AACGAGAT GATC AT CAAG CAGAAG GC AACAAT G CAGGAT TT GGAACAGAGGCGTC CC CAGT TGGAAGAACT CATT ACCGCT GC CCAAAATT T GAAAAACAAGACCAGCAATCAAGAGGCTAGAACAATCATTACGGATCGAATTGAAAGAA T T CAGAAT CAGT GGGATGAAGT ACAAGAAC AC CT TCAGAACCGGAGGCAACAGT TGAAT GAAATGTTAAAGGATTCAACACAATGGCTGGAAGCTAAGGAA GAAGCT GA GCAGGTCTT AGGACAGGCCAGAGCCAAGCTTGAGTCATGGAAGGAGGGTCCCTATACAGTAGATGCAA T C CAAAAGAAAATC AC AGAAAC CAAG CAGT TG GC CAAAGACC TC CG CC AG TG GC AG AC A AATGTAGATGTGGCAAATGACTTGGCCCTGAAACTTCTCCGGGATTATTCTGCAGATGA TACCAGAAAAGTCCACATGATAACAGAGAATATCAATGCCTCTTGGAGAAGCATTCATA AAAGGGTGAGTGAGCGAGAGGCTGCTTT GGAAGAAACT CATAGATTACTGCAACAGTT C CCCCTGGACCTGGAAAAGTTTCTTGCCTGGCTTACAGAAGCTGAAACAACTGCCAATGT CCTACAGGATGCTACCCGTAAGGAAAGGCTCCTAGAAGACTCCAAGGGAGTAAAAGAGC TGAT GAAACAATGGCAAGACCT CCAAGGTGAAAT TGAAGCTCACACAGAT GT TT AT CAC AACCTGGATGAAAACAGCCAAAAAATCCTGAGATCCCTGGAAGGTTCCGATGATGCAGT CC TGTT ACAAAGACGT TT GGAT AACATGAACT TCAAGT GGAGTGAACT TC GGAAAAAGT CT CT CAAC AT TAGGTCCCAT TT GGAAGC CAGT TC TGAC CAGT GGAAGC GT CT GC AC CT T TCTCTGCAGGAACTTCTGGTGTGGCTACAGCTGAAAGATGATGAATTAAGCCGGCAGGC ACCTATTGGAGGCGACTTTCCAGCAGTTCAGAAGCAGAACGATGTACATAGGGCCTTCA AGAGGGAATT GAAAACTAAAGAACCT GTAATCAT GAGTACTCTTGAGACT GT ACGAAT A T T TC TGAC AGAGCAGCCT TT GGAAGGAC TAGAGAAACT CT ACCAGGAGCC CAGAGAGC T GCCTCCTGAGGAGAGAGCCCAGAATGTCACTCGGCTTCTACGAAAGCAGGCTGAGGAGG T CAATACT GAGT GGGAAAAATT GAAC CT GC AC TC CGCT GACT GGCAGAGAAAAATAGAT GAGACC CT TGAAAGAC TCCGGGAACT TCAAGAGGCC AC GGAT GAGCTGGACCTCAAGC T GCGC GAAGCT GAGGTGATCAAGGGATCCTGGCAGCCCGTGGGCGATCTCCTCATTGACT C T CT CC AAGATC AC CT CGAGAAAG TC AAGG CACT TC GAGGAGAAAT TG CG CC TC TGAAA GA GAAC GT GAGC CACGTCAATGAC CT TGCT CGCCAGCTTACCACTT TGGG CATT CAGCT CT CACC GT AT AACCTCAGCACT CT GGAAGACCTGAACACC AGAT GGAAGC TT CT GCAGG TGGCCGTCGAGGACCGAGTCAGGCAGCTGCATGAAGCCCACAGGGACTTTGGTCCAGCA T C TC AG CACT TT CT TT CC AC GT CT GT CC AG GG TC CC TGGGAGAGAG CC AT CT CG CCAAA CAAAGT GC CC TACT AT AT CAAC CACGAGAC TCAAACAACT TGCT GGGACC AT CC CAAAA T GAC AGAGCT CT AC CAGT CT TT AGCT GACC TGAATAAT GT CAGA TT CT CAGC TT AT AGGAC TGCC AT GAAACT CCGAAGAC TGCAGAAGGC CC TT TGCT TGGATC TC TT GAGC CT GT CWSGR Ref. No.: 64320-710.601Identity SequenceAGCT GC AT GT GATGCCTT GGAC CAGC ACAACC TCAAGCAAAATGAC CAGC CC AT GGAT A TCCTGCAGATTATTAATTGTTTGACCACTATTTATGACCGCCTGGAGCAAGAGCACAAC AATTTGGTCAACGTCCCTCTCTGCGTGGATATGTGTCTGAACTGGCTGCTGAATGTTTA T GAT AC GGGACGAACAGGGAGGAT CC GT GT CC TGTCTT TT AAAACT GGCATC AT TT CC C T GTGTAAAGC ACAT TT GGAAGACAAGTACAGATACC TT TT CAAGCAAGTGGCAAGT TC A AC AGGATT TT GT GACCAGCGCAGGCT GGGC CT CC TT CT GCAT GATT CT AT CCAAAT TC C AAGACAGT TGGGTGAAGT TGCATC CT TT GGGGGC AGTAACAT TGAGCCAAGT GT CC GGA GCTGCTTCCAATTTGCTAATAATAAGCCAGAGATCGAAGCGGCCCTCTTCCTAGACTGG ATGAGACTGGAACCCCAGTCCATGGTGTGGCTGCCCGTCCTGCACAGAGTGGCTGCTGC AGAAAC TGCCAAGCAT CAGGCCAAAT GT AACATC TGCAAAGAGT GT CCAATC AT TGGAT T C AGGT AC AGGAGT CT AAAGCACT TT AATT AT GACATCTGCCAAAGCT GC TT TT TT TC T GGTC GAGT TGCAAAAGGCCATAAAAT GC AC TATC CCAT GGTGGAAT AT TGCACT CC GAC TACATCAGGAGAAGATGTTCGAGACT TT GCCAAGGTACTAAAAAACAAAT TT CGAACCA AAAGGT AT TT TGCGAAGCAT CC CC GAAT GGGC TACC TGCCAGTGCAGACT GT CT TAGAG GGGGACAACATGGAAACTCCCGTTACTCTGATCAACTTCTGGCCAGTAGATTCTGCGCC TGCCTCGTCCCCTCAGCTTTCACACGATGATACTCATTCACGCATTGAACATTATGCTA GC AGGC TAGC AGAAAT GGAAAACAGCAATGGATC TT AT CT AAAT GATAGC AT CT CT CC T AATGAGAGCATAGATGAT GAACAT TT GT TAAT CC AGCATT AC TGCCAAAGTT TGAACC A GGACTCCCCCCTGAGCCAGCCTCGTAGTCCTGCCCAGATCTTGATTTCCTTAGAGAGTG AGGAAAGAGGGGAGCTAGAGAGAATCCTAGCAGATCTTGAGGAAGAAAACAGGAATCTG CAAGCAGAATATGACCGTCTAAAGCAGCAGCACGAACATAAAGGCCTGTCCCCACTGCC GT CC CC TC CT GAAATGAT GCCC AC CT CT CC CC AGAGTCCCC GGGAT GC TGAGCT CATT G CTGAGGCCAAGCTACTGCGTCAACACAAAGGCCGCCTGGAAGCCAGGATGCAAATCCTG GAAGACCACAATAAACAGCTGGAGTCACAGTTACACAGGCTAAGGCAGCTGCTGGAGCA ACCCCAGGCAGAGGCCAAAGTGAATGGCACAACGGTGTCCTCTCCTTCTACCTCTCTAC AGAGGTCCGACAGCAGTCAGCCTATGCTGCTCCGAGTGGTTGGCAGTCAAACTTCGGAC TCCATGGGTGAGGAAGATCTTCTCAGTCCTCCCCAGGACACAAGCACAGGGTTAGAGGA GGTGAT GGAGCAACTCAACAAC TC CT TC CC TA GT TCAAGAGGAAGAAATACC CC TGGAA AGCCAATGAGAGAGGACACAAT GT AGGAAGTCTT TTCCACATGGCAGATGAT TT GGGCA GAGCGATGGAGTCCTTAGTATCAGTCATGACAGATGAAGAAGGAGCAGAATAAATGTTT T ACAAC TC CT GATT CCCGCATG GT TT TT AT AATATT CATACAACAAAGAGGATT AGACA GT AA GA GT TT ACAAGAAATAAATC TATATT TT TGTGAAGGGT AGTGGT AT TA TA CT GT A GATTTCAGTAGTTTCTAAGTCTGTTATTGTTTTGTTAACAATGGCAGGTTTTACACGTC TATGCAATTGTACAAAAAAGTTATAAGAAAACTACATGTAAAATCTTGATAGCTAAATA ACTTGCCATTTCTTTATATGGAACGCATTTTGGGTTGTTTAAAAATTTATAACAGTTAT AAAGAAAGAT TGTAAACT AAAGTGTGCT TT AT AAAAAAAAGT TGTT TATAAAAACC CC T AAAAACAAAACAAACACACACACACACACATACACACACACACACAAAACTTTGAGGCA GCGCATTGTTTTGCATCCTTTTGGCGTGATATCCATATGAAATTCATGGCTTTTTCTTT T T TT GCAT AT TAAAGATAAGAC TT CC TC TACC AC CACACCAAAT GACT AC TACACACT G CTCATTTGAGAACTGTCAGCTGAGTGGGGCAGGCTTGAGTTTTCATTTCATATATCTAT AT GT CT AT AAGT AT AT AAAT AC TA TA GT TATATAGATAAAGAGATACGAATT TC TA TAG AC TGAC TT TT TCCATT TT TTAAAT GT TC AT GT CACATCCT AATAGAAAGAAATT AC TT C TAGTCAGTCATCCAGGCTTACCTGCTTGGTCTAGAATGGATTTTTCCCGGAGCCGGAAG CCAGGAGGAAACTACACCACACTAAAACATTGTCTACAGCTCCAGATGTTTCTCATTTT AAACAACT TT CCACTGACAACGAAAGTAAAGTAAAGTATTGGATTT TT TTAAAGGGAAC AT GT GAAT GAATACACAGGACT TATT AT AT CAGAGTGAGTAATCGGTT GGTT GGTT GAT T GAT TGAT TGAT TGAT ACAT TC AGCT TC CT GC TGCT AGCAAT GCCACGAT TT AGAT TT A ATGATGCTTCAGTGGAAATCAATCAGAAGGTATTCTGACCTTGTGAACATCAGAAGGTA T T TT TT AACT CCCAAGCAGT AGCAGGAC GATGAT AGGGCT GGAGGGCT AT GGAT TC CCA GC CC AT CC CT GT GAAGGAGT AGGC CACT CT TT AAGT GAAGGATT GGAT GATT GT TC AT A AT AC AT AAAGTT CT CT GT AATT ACAACT AAAT TATT AT GCCCTCTT CT CACAGT CAAAA GGAACTGGGTGGTTTGGTTTTTGTTGCTTTTTTAGATTTATTGTCCCATGTGGGATGAG T T TT TAAATGCC ACAAGACATAAT TTAAAATAAATAAACT TT GGGAAAAGGT GT AAAAC AGTAGC CC CATCACAT TT GT GATACT GACAGGTATCAACCCAGAAGCC CATGAACT GT G TTTC CATC CT TTGCATTTCTCTGC GAGT AGTTCCACACAGGTTTGT AAGT AAGT AAGAA AGAAGGCAAATT GATT CAAATGTT ACAAAAAAAC CCTT CT TGGT GGAT TAGACAGGTT A AATATATAAACAAACAAACAAAAA TT GC TCAAAAAAGAGGAGAAAAGC TCAAGAGGAAA AGCTAAGGACTGGTAGGAAAAAGCTTTACTCTTTCATGCCATTTTATTTCTTTTTGATT T T TAAATC AT TCAT TCAATAGATACC AC CGTGTGACCT AT AATT TT GCAAAT CT GT TAG CT CT GACATCAAGTGTAATTAGCT TT TGGAGAGT GGGCTGACATCAAGTGTAAT TAGCT TTTGGA GAGT GGGTTTTGTCCATTATTAAT AATT AATTAATTAACATCAAACACGGCTTCTCATGCTATTTCTACCTCACTTTGGTTTTGGGGTGTTCCTGATAATTGTGCACACCTGWSGR Ref. No.: 64320-710.601Identity Sequence AGTTCACAGCTTCACCACTTGTCCATTGCGTTATTTTCTTTTTCCTTTATAATTCTTTC T T TT TC CT TC AT AATT TT CAAAAGAAAACC CAAAGCTCTAAGGTAACAAATT AC CAAAT TACATGAAGATTTGGTTTTTGTCTTGCATTTTTTTCCTTTATGTGACGCTGGACCTTTT CT TT AC CCAAGGAT TT TT AAAACT CAGATT TAAAACAAGGGGTT AC TT TACATC CT AC T AAGAAGTT TAAGTAAGTAAG TT TCAT TCTAAAAT CAGAGGTAAATAGAGT GCAT AAAT A AT TT TGTT TTAATCTTTTTGTT TT TCTT TT AGACACATTAGCTCTGGAGT GA GT CT GT C ATAATATTTGAACAAAAATTGA GA GCTTTATTGCTGCATTTTAAGCAT AATT AATT TGG ACATTATTTCGTGTTGTGTTCTTTATAACCACCAAGTATTAAACTGTAAATCATAATGT AACT GAAGCATAAACATCACAT GGCATGTT TT GT CATTGT TTTCAGGT ACTGAGTT CT T AC TT GA GT AT CATAAT AT AT TGTGTT TT AACACCAACACT GT AACATT TACGAATT AT T T T TT TAAACT TCAGTT TT ACTGCATT TT CACAAC AT AT CAGACT TC AC CAAATATATGC CT TACT AT TGTATTATAGTACT GCTT TACT GT GT ATCTCAATAAAGCACGCAGT TATGT TACAAAAAA(SEQ ID NO: 1)Exemplary MLWWEEVEDCYEREDVQKKTFTKWVNAQFSKFGKQHIENLFSDLQDGRRLLDLLEGLTG QKLPKEKGSTRVHALNNVNKALRVLQNNNVDLVNIGSTDIVDGNHKLTLGLIWNIILHWhuman, full- QVKNVMKNIMAGLQQTNSEKILLSWVRQSTRNYPQVNVINFTTSWSDGLALNALIHSHR PDLFDWNSWCQQSATQRLEHAFNIARYQLGI EKLLDPEDVDTTYPDKKS ILMYITSLFlength, wildQVLPQQVS IEAIQEVEMLPRPPKVTKEEHFQLHHQMHYSQQITVSLAQGYERTSSPKPR type dystrophin FKSYAYTQAAYVTTSDPTRSPFPSQHLEAPEDKS FGSSLMESEVNLDRYQTALEEVLSW LLSAEDTLQAQGEISNDVEWKDQFHTHEGYMMDLTAHQGRVGNILQLGSKLIGTGKLSprotein, EDEETEVQEQMNLLNSRWECLRVASMEKQSNLHRVLMDLQNQKLKELNDWLTKTEERTR KMEE EP LG PD LE DL KRQVQQHKVL QE DL EQ EQVRVN SL THMVWVD ES SGDH AT AALE EDystrophin-4, QLKVLGDRWANICRWTEDRWVLLQDILLKWQRLTEEQCLFSAWLSEKEDAVNKIHTTGF variant Dp427m KDQNEMLSSLQKLAVLKADLEKKKQSMGKLYSLKQDLLSTLKNKSVTQKTEAWLDNFAR CW DN LVQKLE KS TAQI SQAVTT TQ PS LT QT TVME TVTT VT TREQ IL VKHAQE EL PP PP P(SEQ ID NO: QKKRQITVDSEIRKRLDVDITELHSWITRSEAVLQSPEFAIFRKEGNFSDLKEKVNAIE REKAEKFRKLQDASRSAQALVEQMVNEGVNADSIKQASEQLNSRWIEFCQLLSERLNWL2) EYQNNI IAFYNQLQQLEQMTTTAENWLKIQPTTPSEPTAIKSQLKI CKDEVNRLSDLQP QIERLKIQSIALKEKGQGPMFLDADFVAFTNHFKQVFSDVQAREKELQTI FDTLPPMRY QETMSAIRTWVQQSETKLSIPQLSVTDYEIMEQRLGELQALQSSLQEQQSGLYYLSTTV KEMSKKAPSEISRKYQSEFEEIEGRWKKLSSQLVEHCQKLEEQMNKLRKIQNHIQTLKK WMAEVDVFLKEEWPALGDSEILKKQLKQCRLLVSDIQTIQPSLNSVNEGGQKIKNEAEP EFASRLETELKELNTQWDHMCQQVYARKEALKGGLEKTVSLQKDLSEMHEWMTQAEEEY LERDFEYKTPDELQKAVEEMKRAKEEAQQKEAKVKLLTESVNSVIAQAPPVAQEALKKE LETLTTNYQWLCTRLNGKCKTLEEVWACWHELLSYLEKANKWLNEVEFKLKTTENI PGG AEEI SEVLDSLENLMRHSEDNPNQIRILAQTLTDGGVMDELINE ELET FNSRWREL HEE AVRRQKLLEQSIQSAQETEKSLHLIQESLTFIDKQLAAYIADKVDAAQMPQEAQKIQSD LTSHEI SLEEMKKHNQGKEAAQRVLSQIDVAQKKLQDVSMKFRLFQKPANFEQRLQESK M I LD EVKMHL PALE TKSVEQEVVQ SQ LNHCVN LY KS LS EVKS EVEMVI KT GRQI VQ KKQ TENPKELDERVTALKLHYNELGAKVTERKQQLEKCLKLSRKMRKEMNVLTEWLAATDME LTKRSAVEGMPSNLDSEVAWGKATQKEIEKQKVHLKSITEVGEALKTVLGKKETLVEDK L S LL NS NW I AVT S RAE EW LN LL LE YQ KHME TF DQNVDH I T KW 11 QADT LL DE SE KK KP Q QKEDVLKRLKAELNDIRPKVDSTRDQAANLMANRGDHCRKLVEPQI SELNHRFAAI SHR IKTGKASI PLKELEQFNSDIQKLLEPLEAEIQQGVNLKEEDFNKDMNEDNEGTVKELLQ RGDNLQQRITDERKREEIKIKQQLLQTKHNALKDLRSQRRKKALEI SHQWYQYKRQADD LLKCLDDIEKKLASLPEPRDERKIKEIDRELQKKKEELNAVRRQAEGLSEDGAAMAVEP TQIQLSKRWREIESKFAQFRRLNFAQIHTVREETMMVMTEDMPLEI SYVPSTYLTEITH VSQALLEVEQLLNAPDLCAKDFEDLFKQEESLKNIKDSLQQS SGRIDI IHSKKTAALQS ATPVERVKLQEALSQLDFQWEKVNKMYKDRQGRFDRSVEKWRRFHYDIKI FNQWLTEAE QFLRKTQI PENWEHAKYKWYLKELQDGIGQRQTVVRTLNATGEEIIQQSSKTDASILQE KLGSLNLRWQEVCKQLSDRKKRLEEQKNILSEFQRDLNEFVLWLEEADNIAS IPLEPGK EQQLKEKLEQVKLLVEELPLRQGI LKQLNETGGPVLVSAPISPEEQDKLENKLKQTNLQ WIKVSRALPEKQGEIEAQIKDLGQLEKKLEDLEEQLNHLLLWLSPIRNQLEIYNQPNQE GPFDVKETEIAVQAKQPDVEEILSKGQHLYKEKPATQPVKRKLEDLSSEWKAVNRLLQE LRAKQP DL AP GLTT IGAS PTQTVT LVTQ PVVT KE TAI S KLEMPS SLML EVPALADFNRA WTELTDWLSLLDQVIKSQRVMVGDLEDINEMI IKQKATMQDLEQRRPQLEEL ITAAQNL KNKTSNQEARTI ITDRIERIQNQWDEVQEHLQNRRQQLNEMLKDSTQWLEAKEEAEQVL GQ ARAK LE SW KE GP YT VD Al QK KI TE TKQL AK DL RQ WQ TN VD VAND LALK LL RD YS AD DTRKVHMITENINASWRSIHKRVSEREAALEETHRLLQQFPLDLEKFLAWLTEAETTANVWSGR Ref. No.: 64320-710.601Identity SequenceLQDATRKERLLEDSKGVKELMKQWQDLQGEIEAHTDVYHNLDENSQKI LRSLEGSDDAV LLQRRLDNMNFKWSELRKKSLNIRSHLEASSDQWKRLHLSLQELLVWLQLKDDELSRQA PIGGDFPAVQKQNDVHRAFKRELKTKEPVIMSTLETVRIFLTEQPLEGLEKLYQEPREL PPEERAQNVTRLLRKQAEEVNTEWEKLNLHSADWQRKIDETLERLRELQEATDELDLKL RQAEVI KGSWQPVGDLLI DS LQDHLEKVKALRGE IAPLKENVSHVNDLARQLTTLGIQL SPYNLSTLEDLNTRWKLLQVAVEDRVRQLHEAHRDFGPASQHFLSTSVQGPWERAI SPN KVPYYINHETQTTCWDHPKMTELYQSLADLNNVRFSAYRTAMKLRRLQKALCLDLLSLS AACD AL DQ HN LKQN DQ PMD I LQ 11 NG LT T I YD RL EQ EHNN LVNVPL CVDM CL NW LL NV Y DTGRTGRIRVLSFKTGIISLCKAHLEDKYRYLFKQVASSTGFCDQRRLGLLLHDSIQIP RQLGEVASFGGSNIEPSVRSCFQFANNKPEIEAALFLDWMRLEPQSMVWLPVLHRVAAA ETAKHQAKCNICKECPIIGFRYRSLKHFNYDICQSCFFSGRVAKGHKMHYPMVEYCTPT T S GE DVRD FAKVLKNKFRTKRY FAKH PRMG YL PVQT VL EGDNME TP VT LI NF WP VD SAP ASSPQLSHDDTHSRIEHYASRLAEMENSNGSYLNDSISPNESIDDEHLLIQHYCQSLNQ DSPLSQPRSPAQILISLESEERGELERILADLEEENRNLQAEYDRLKQQHEHKGLSPLP SPPEMMPTSPQSPRDAELIAEAKLLRQHKGRLEARMQILEDHNKQLESQLHRLRQLLEQ PQAEAKVNGTTVSSPSTSLQRSDS SQPMLLRVVGSQTSDSMGEEDLLSPPQDTSTGLEE VMEQLNNS FPSSRGRNTPGKPMREDTM(SEQ ID NO: 2)Duchenne Muscular Dystrophy and Becker Muscular Dystrophy

[0044] Duchenne Muscular Dystrophy (DMD) is a severe X-linked recessive neuromuscular disorder effecting approximately 1 in 4,000 live male births. Patients are generally diagnosed by the age of 4, and wheelchair-bound by the age of 10. Most patients do not live past the age of 25 due to cardiac and / or respiratory failure. Existing treatments are generally palliative. The most common treatment for DMD comprises steroids, which are used to slow the loss of muscle strength. However, because most DMD patients start receiving steroids early in life, the treatment delays puberty and further contributes to the patient's diminished quality of life. There remains a critical need for developing safe and effective treatments for DMD, which is among the most prevalent and debilitating genetic disorders.

[0045] DMD is caused by mutations in the dystrophin gene (Chromosome X: 31,117,228-33,344,609 (Genome Reference Consortium - GRCh38 / hg38)). DMD is caused by a variety of mutations within the dystrophin gene that result in premature stop codons, and therefore, a truncated dystrophin protein. Truncated dystrophin proteins do not contain the C-terminus, and therefore cannot provide the structural support necessary to withstand the stress of muscle contraction. As a result, the muscle fibers pull themselves apart, which leads to muscle wasting. In some embodiments, mutations in the dystrophin gene causative of DMD or BMD can comprise one or both of E2910V and N2912D. In one non-limiting embodiment, any compositions described herein can be administered to a subject in need thereof, wherein the subject has a E2910V mutation in dystrophin, in which the 2910thresidue comprising glutamic acid is mutated to valine. In another non-limiting embodiment, any compositions described herein can be administered to a subject in need thereof, wherein the subject has a N2912D mutation in dystrophin, in which the 2912thresidue comprising asparagine is mutated to aspartic acid. In yet another non-limiting embodiment, any compositions described herein can be administered to a subject in need thereof, wherein the subject has both a E2910V and N2912D mutation in dystrophin. In some embodiments, mutations in the dystrophin gene causative of DMD or BMD can comprise one or more deletion mutations resulting in a frameshift mutation. In some embodiments, mutations in the dystrophinWSGR Ref. No.: 64320-710.601gene causative of DMD or BMD can comprise one or more deletion mutations in one or more exons comprising exons 2-20 and 45-55 resulting in a frameshift mutation. In certain embodiments, a mutation causative of DMD or BMD comprises one or more deletion mutations in one or more of exons 4, 8, 12, 17, 19, 44, 45, 48 and 51 resulting in a frameshift mutation. In some embodiments, a mutation causative of DMD or BMD comprises one or more deletion mutations in one or more of exons 19, 45, 48, and 51 resulting in a frameshift mutation. In an embodiment, a mutation causative of DMD or BMD comprises one or more deletion mutations in exon 51 resulting in a frameshift mutation. In one embodiment, a mutation causative of DMD or BMD comprises at least one deletion mutation in exon 51 resulting in a frameshift mutation. In one embodiment, a mutation causative of DMD or BMD comprises at least two deletion mutations in exon 51 resulting in a frameshift mutation. In one embodiment, a mutation causative of DMD or BMD comprises at least three deletion mutations in exon 51 resulting in a frameshift mutation. In another embodiment, a mutation causative of DMD or BMD comprises one or more deletion mutations in exon 19 resulting in a frameshift mutation. In another embodiment, a mutation causative of DMD or BMD comprises one or more deletion mutations in exon 45 resulting in a frameshift mutation. In one instance, a mutation causative of DMD or BMD comprises one or more deletion mutations in exon 48 resulting in a frameshift mutation. In some embodiments, the frameshift mutation results in the expression of a truncated, partially function dystrophin protein, or a truncated, nonfunctional dystrophin protein.

[0046] Becker Muscular Dystrophy (BMD) is a less severe form of muscular dystrophy compared to DMD. While BMD is also caused by mutations within the dystrophin gene, BMD mutations maintain the dystrophin reading frame. BMD dystrophin proteins contain internal deletions but also retain portions of both the N- and C-termini. Therefore, the BMD dystrophin protein is shorter than the wild-type protein but can still function as a linker between the actin filaments and the extracellular matrix. Depending on the size of the internal deletion, BMD patients may have only minor symptoms. As a result, most research efforts have been focused on converting the severe DMD phenotype to a less severe BMD phenotype. In some embodiments, mutations in the dystrophin gene causative of BMD can comprise point mutations in the rod domain of the dystrophin gene, for example, in the rod domain repeat 23 (R23) encoded by exon 59 and corresponding to residues 2800-2939 of the wild-type, full-length dystrophin protein. In some embodiments, a mutation causative of BMD comprises one or more deletion mutations resulting in a frameshift mutation. In one embodiment, a mutation causative of BMD comprises one or more deletion mutations in exon 51 resulting in a frameshift mutation. In another embodiment, a mutation causative of BMD comprises at least one deletion mutation in exon 51 resulting in a frameshift mutation. In some embodiments, a mutation causative of BMD comprises one or more deletion mutations resulting in an in-frame mutation. In some embodiments, the in-frame mutation results in the expression of a truncated but functional dystrophin protein.

[0047] Duchenne muscular dystrophy affects the heart as well as skeletal muscle. Indeed, cardiomyopathy is the leading cause of death in Duchenne patients. There are no approved treatments for the cardiomyopathy, and novel Duchenne-specific experimental approaches such as exon skipping do notWSGR Ref. No.: 64320-710.601benefit the heart. Disclosed herein are compositions and formulations of neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPC secretome, or nMPC exosomes for therapeutic regeneration after myocardial infarction and that can reverse the key pathophysiological hallmarks and symptoms of Duchenne cardiomyopathy (e.g, oxidative stress, inflammation, fibrosis, and mitochondrial dysfunction). Exosomes secreted by human nMPCs can reverse abnormalities of calcium cycling and mitochondrial respiration in human Duchenne cardiomyocytes.

[0048] Loss of functional dystrophin in the heart leads to impairment in nitric oxide signaling, membrane instability, and micro-tears in the membrane occurring with muscle contraction which allow an influx of calcium into cells. Excessive calcium uptake by mitochondria and impaired nitric oxide signaling leads to mitochondrial dysfunction and increased reactive oxygen species production, ultimately resulting in necrosis and cell death. As a result, multiple inflammatory pathways are activated and lead to fibrosis. Fibrosis in the heart occurs early in the disease, contributes to cardiac dysfunction, and is associated with mortality.

[0049] Given the heart's limited regenerative capacity, progenitor cell-derived therapies with the nMPCs, nMPC secretome, or nMPC exosomes described herein, which have a multimodal mechanism of action capable of targeting the critical pathological mechanisms of dystrophinopathy (e.g, DMD, BMD, etc.), represent a promising therapeutic approach for symptoms (e.g, cardiomyopathy, muscle weakness, etc.) associated with this disease. nMPCs, nMPC secretome, or nMPC exosomes can, for example, facilitate the growth of healthy heart muscle and decrease scar formation after myocardial infarction. The goal of using the compositions comprising nMPCs, an nMPC secretome, and / or nMPC exosomes is not to replace dystrophin, but rather, to offset the pathophysiological consequences of dystrophin deletion, by recruiting regenerative factors, reversing fibrosis, and / or targeting inflammation.Emery-Dreifuss Muscular Dystrophy

[0050] Emery-Dreifuss muscular dystrophy (EDMD) is typically inherited as an X-linked recessive or autosomal dominant disorder with more males being affected than females. The X-linked form of EDMD is caused by a mutation of the EMD gene in the Xq28 region of the X chromosome, which is the gene locus that encodes for a nuclear membrane protein called emerin. Rare autosomal dominant form of EDMD can be caused by subsequent mutations in lamin A / C when there are mutations on the chromosome lq21 in the SYNE1 and SYNE2 genes that encode for the nuclear envelope proteins, nesprin- 1 and nesprin-2, as well as in transmembrane protein 43 (TMEM43) or LUMA.

[0051] EMDM may also be caused, for example, but a hemizygous pathogenic variant in a EMD gene or a FHL1 gene, a heterozygous pathogenic (or likely pathogenic) variant in a LMNA gene, or a biallelic pathogenic variant in a LMNA gene. Symptoms of EMDM include, but are not limited to, stiffness of joints, wasting or weakening of muscles (e.g, muscles in the shoulders, upper arms and calves), heart conditions (e.g., palpitations, presyncope, syncope, poor exercise tolerance, congestive heart failure, variable cardiac rhythm disturbances, bradycardia, atrial ventricular conduction defects, heart blockage, ventricular myocardial disease with failure and stroke, secondary to cardiac arrhythmia etc.), fainting, an awkward gait, a tendency for toe walking, fixed equinus deformities of the ankles, flexion contractures ofWSGR Ref. No.: 64320-710.601the elbows, extension contracture of the neck, tightness of the lumbar paravertebral muscles, respiratory insufficiency, etc.Facioscapulohumeral Muscular Dystrophy

[0052] Facioscapulohumeral muscular dystrophy (FSH) is an autosomal dominant disorder caused by deletions of a 3.3-kb tandem repeat (D4Z4) in the sub-telomeric region at the 4q35 locus. In a normal patient, there are 11 to 100 D4Z4 repeats. When there are fewer repeats (e.g., <10 repeat units), chromatin remodeling leads to decreased methylation, thereby turning on DUX4 expression and causing disease. FSH occurs in chromosomes that carry a pLAMl poly adenylate site distal to the last D4Z4 repeat. These changes create a “permissive” haplotype which allows for the expression of DUX4. Alternatively, in the 5% to 10% of patients who do not have a mutated 4q3 locus, there is a mutation in the SMCHD1 gene (on chromosome 18p) that can lead to hypomethylation of D4Z4, causing FSH type 2. Symptoms of FSH include, but are not limited to, muscle wasting (e.g, of biceps, triceps, clavicular head of the pectoral muscles, abdomen, ankles, tibialis anterior muscle, etc. ), restrictive lung disease, intellectual disability, epilepsy, facial weakness, delayed motor milestones, progressive limb-girdle pattern of weakness, marked muscle wasting, hyperlordosis, loss of ambulation, ptosis, head drop, joint contractures, cardiomyopathy, weakness of the orbicularis oris muscle, limited facial expression, transverse smile, incomplete burying of eyelashes, forced eye closure, scapular winging, hearing loss, retinal vasculopathy (Coats disease), retinal detachment, blindness etc.Oculopharyngeal Muscular Dystrophy

[0053] Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder is which is predominantly found in Quebec, Germany, and Uruguay (Montevideo) as well as the Spanish -American populations of Colorado, New Mexico, and Arizona, Ashkenazi Jews, and those of French -Canadian descent. OPMD is caused by a mutation and expansion of GCG repeats on chromosome 14ql 1.2- 13 in the gene that encodes for polyadenylate-binding protein nuclear 1 PABPN1). Mutations can contain between 8 and 13 repeats. Longer expansion repeats of PABPN1 cause earlier onset of disease.Homozygous mutations cause more severe OPMD. Symptoms of OPMD include, but are not limited to, progressive muscle wasting, atrophy of myocytes (affecting the eye and periocular muscles), extraocular muscle weakness, ptosis, disruptive eye movements dysphagia, impaired swallow efficiency, reduced pharyngeal constriction, reduced speed of hyoid movement, airway closure, oral regurgitation, nasal regurgitation, aspiration, post-swallow pharyngeal residue, esophageal retention, difficulty swallowing, weight loss, malnutrition, aspiration, facial weakness, hip weakness, shoulder weakness, change in voice quality, excessive fatigue, impaired cognitive function, extreme emaciation starvation, death, etc.Myotonic dystrophy type 1 (DM1)

[0054] Myotonic dystrophy type 1 (DM1) is a complex, multisystemic neuromuscular disorder with several pathological phenotypes, disease severities and ages of onset.

[0055] Myotonic dystrophy type 1 (DM1) is a common form of muscular dystrophy among adults, although it can also affect children. The disease displays a multisystemic complexity, affecting severalWSGR Ref. No.: 64320-710.601body systems, besides the skeletal muscle, such as the heart, the eye, the respiratory system, the endocrine system and the central nervous system (CNS).

[0056] DM1 is an autosomal dominant disease caused by unstable expanded cytosine-thymine-guanine (CTG) repeats within the 3' untranslated region (3' UTR) of the DMPK (Dystrophia Myotonica Protein Kinase,' OMIM* 605377) gene at chromosome 19ql3.3. In stable, unaffected individuals, the length of the CTG expansion ranges from five to thirty-four repeats, which are stably inherited and have a low mutation rate. DM1 patients have CTG expansions exceeding 50 repeats and extending from hundreds to thousands of repeats becoming highly unstable and often expanding further in both germline and somatic cells. DM1 alleles also include a ‘premutation range’ with CTG repeat lengths ranging from 38 to 49. Individuals with permutations show none or few mild symptoms but are more likely to pass a pathologically expanded mutant allele to the next generations. DM1 displays the phenomenon of anticipation, characterized by larger repeat expansions from one generation to the next, resulting in an earlier onset and more pronounced clinical features.

[0057] DM1 is classified according to the age of onset and the severity of disease symptoms. DM1 is classified mild, classic or severe based on severity and clinically categorized as congenital -onset, infantile-onset, juvenile-onset, adult-onset and late-onset. Each phenotype is associated with CTG repeat expansions larger than 100 and up to several thousands, with major overlap in CTG repeat sizes across different phenotypes.

[0058] Congenital-onset DM1 is the most severe form and is characterized by a CTG repeat length greater than 1000 repeats. The first clinical symptoms appear prenatally or at birth, with an estimated incidence ranging from 2 to 28 per 100,000 live births. In the ‘severe’ form, also referred to as congenital DM1, symptoms can include hypotonia, generalized muscle weakness and myopathic facies, which may result in feeding difficulties and require respiratory support. In contrast to juvenile- and adult-onset, myotonia is typically absent in congenital DM1 in early childhood. Symptoms of DM1 include, but are not limited to, muscle weakness (distal and facial weakness of arms, hands, ankles, jaw, tongue or neck flexors), myotonia (often affecting the hands, tongue and jaw due to slow muscle relaxation), distal progressive muscle wasting, distal progressive muscle weakness, facial involvement, bulbar involvement, high palate, dysphonia, chronic pain (e.g., of the hands and feet), small fiber neuropathy, large fiber neuropathy, an increased risk for benign tumors, an increased risk for malignancies, and higher complications of adverse reactions to anesthesia and analgesic drugs relative to the general population, progressive cognitive decline, changes in brain white matter, fatigue, droopy eyelids, handshaking, breathing difficulties, swallowing difficulties, etc.Congenital muscular dystrophy

[0059] Congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance. The most common subtypes of CMD are MDC1 A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha- dystrogly can (Fukuyama CMD, Muscle-eye-brain disease, WalkerWSGR Ref. No.: 64320-710.601Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome. Fukuyama congenital muscular dystrophy (FCMD) is an inherited condition that predominantly affects the muscles, brain, and eyes. FCMD is seen almost exclusively in Japan. FCMD is caused by mutations in the FKTN gene which encodes fukutin. The most common mutation in the FKTN gene reduces the amount of fukutin produced within cells. A shortage of fukutin likely prevents the normal modification of a-dystroglycan, which disrupts that protein's normal function. Symptoms of CMDs include, but are not limited to, congenital hypotonia, delayed motor development, progressive muscle weakness, weak cry, poor feeding, weak muscle tone (hypotonia), damaged muscle fibers, atrophy of the skeletal muscles, weakness of the facial muscles, droopy eyelids (ptosis), an open mouth, joint deformities (contractures), impaired brain development, cobblestone lissencephaly, delayed development of speech and motor skills, moderate to severe intellectual disability, impaired social skills, seizures, impaired vision, eye abnormalities, progressive heart problems, swallowing difficulties, aspiration pneumonia, etc.Limb-girdle muscular dystrophy (LGMD)

[0060] Limb-girdle muscular dystrophies (LGMDs) are caused by mutations in multiple genes. Some forms are inherited in a dominant fashion, while others occur recessively. They are caused by a mutation in a gene encoding a protein, which is specific to each subtype. LGMD inheritance is autosomal.Symptoms of LGMDs include, but are not limited to, deterioration (atrophy) of skeletal muscles (limb-girdle muscle deterioration), late-onset distal myopathy (affecting ankles, feet or calves), respiratory insufficiency, cardiac failure, cardiac arrhythmia, skeletal muscle weakness due to impaired mitochondrial form and function, muscle rippling, myalgia, HyperCKemia, ankle contracture, calf hypertrophy, exercise intolerance, muscular cramps, fat infiltration, increased number of internal nuclei and rimmed vacuoles, cardiomyopathy, fatty replacement in semitendinosus, gastrocnemius and soleus, distal weakness, facial weakness, bulbar weakness, a pelvic lower girdle weakness, atrophy of the axial muscle and shoulder girdle, fatty replacement of fibers in pelvic and thigh muscles, cognitive impairment, decrease in a-dystroglycan glycosylation, myopia, epilepsy, cataracts, etc.Autosomal dominant LGMDs

[0061] LGMD 1A occurs due to a mutation in the ATKO7' gene, responsible for myotilin synthesis which cross-links actin filaments and controls sarcomere assembly. LGMD IB occurs due to mutations in the LMNA gene coding for Lamin A / C. LGMD 1C occurs due to mutations in the CAV3 gene, causing a caveolin-3 deficiency. LGMD ID (now LGMD DI) occurs due to a mutation in the DNAJB6 gene, which encodes for a co-chaperone protein. LGMD IE occurs due to mutations in the DES gene encoding for desmin. LGMD IF (now LGMD D2) occurs due to mutations in the TNPO3 gene coding for transportin 3. LGMD 1G (now LGMD D3) is caused by a defect in the heterogenous nuclear ribonucleoprotein D-like (hnRNPDL) protein and patient muscles show rimmed vacuoles. LGMD 1H is an autosomal dominant type of LGMD with an alteration in a gene situated in chromosome 3 (3p23-p25). LGMD II (now LGMD D4) occurs due to dominant mutations in the CAPN3 gene, encoding for calpain 3.WSGR Ref. No.: 64320-710.601

[0062] Bethlem myopathy (now LGMD D5) is now also classified as an LGMD and occurs due to a dominant mutation in COL6A1, COL6A2 or COL6A3 genes, encoding for the Collagen 6 protein that plays a role in extracellular matrix structure and muscle regeneration.Autosomal Recessive LGMDs

[0063] LGMD 2 A (now LGMD Rl) occurs due to recessive mutations in CAPN3, a gene encoding for calpain 3. LGMD 2B (LGMD R2) is associated with mutations in the DYSF gene that impair the synthesis of dysferlin. LGMD 2C (LGMD R5) occurs due to mutations in the SGCG gene, which synthetizes the y-Sarcoglycan protein. This protein is part of the DAP complex and plays a role in the cytoskeleton extracellular matrix link. LGMD 2D (LGMD R3) occurs due to a mutation in the SGCA gene of the sarcoglycan complex: the gene responsible for the synthesis of the a-Sarcoglycan protein. LGMD 2E (LGMD R4) occurs due to a mutation in the SGCB gene, related to the -Sarcoglycan protein. LGMD 2F (LGMD R6) occurs due to a mutation in the SGCD gene coding for the 5-Sarcoglycan protein. LGMD 2G (LGMD R7) occurs due to mutations in the TCAP gene encoding for telethonin, which plays a role in myofibrillogenesis in interaction with titin in the sarcomeric Z-disk. LGMD 2H (LGMD R8) occurs due to mutations in the TRIM32 gene, which codes for the tripartite motif-containing protein 32 responsible for the movement of Ca2+in skeletal muscles. LGMD 21 (LGMD R9) occurs due to mutations in the FKRP gene, coding for fukutin-related protein. This protein is necessary for the glycosylation of a-dystroglycan. LGMD 2J (LGMD RIO) occurs due to mutations in the TTN gene. LGMD 2K (LGMD Rll) and LGMD 2N (LGMD R14) occurs due to mutations in the POMT1 and POMT2 genes, respectively. These genes allow for the synthesis of protein O-mannosyltransferase 1 and 2, of which co-expression is necessary for O-mannosylation, an important reaction in a-dystroglycan. LGMD 2L (LGMD R12) is associated with mutations in the ANO5 gene, which encodes for the Anoctamin 5 protein necessary for achieving functional calcium-activated chloride channels in the muscles. LGMD 2M (LGMD R13) occurs due to a mutation in the FKTN gene. The fukutin protein also plays a role in the glycosylation of a-dystroglycan. LGMD 2N (LGMD R14) occurs due to a mutation in the POMT2 gene necessary for the synthesis of protein O-mannosyltransferase 2. LGMD 20 (LGMD R15) occurs due to mutations in the POMGnTl gene, which codes for protein 0-mannose beta-1, 2-Nacetylglucosaminyltranserase 1. Former POMGNT2-related muscular dystrophy (LGMD R24) was also called Walker-Warburg syndrome or muscle-eye-brain disease and occurs due to a mutation in the POMGnT2 gene, encoding for protein O-mannose beta-l,2-Nacetylglucosaminyltranserase 2. LGMD 2P (LGMD R16) occurs due to mutations in the DAG1 gene, encoding for dystroglycan, a protein that is part of the dystroglycan complex. LGMD 2Q (LGMD R17) occurs due to a mutation in the PLEC1 gene, which encodes for the synthesis of the plectin protein. LGMD 2S (LGMD Rl 8) occurs due to mutations in the TRAPPCI 1 gene, which encodes for transport protein particle complex 11. LGMD 2T (LGMD R19) occurs due to mutation in the GMPPB gene, encoding for the GDP-mannose pyrophosphorylase B protein. Its function is to produce GDP-mannose for the O-mannosylation of a-dystroglycan. LGMD2U (LGMDR20) occurs due to mutations in the ISPD gene. Its protein is isoprenoid synthase, responsible for glycosylation of a-dystroglycan. LGMD2V occurs due to mutations in the GA A gene. This encodes for a-WSGR Ref. No.: 64320-710.6011,4-Glucosidase, an important protein for lysozyme function. LGMD2W occurs due to mutations in the LIMS2 gene, which synthetizes Lim and senescent cell antigen-like domains 2 protein. LGMD2X occurs due to mutations in the BVES gene for blood vessel endocardial substance. This encodes for Popeye domain-containing protein 1 (POPDC1) that is involved in the structure and function of cardiac and skeletal muscle cells. LGMD2Y occurs due to mutations in the T0R1A1P1 gene, known for the Torsin 1 A- interacting protein 1. LGMD2Z (LGMDR21) occurs due to mutations in the POGLUT1 gene for protein O-glucosyltransferase 1, which is involved in protein transport. Bethlem myopathy recessive (LGMDR22) occurs due to mutations in collagen 6 genes COL6A1, COL6A2, and COL6A3, which play roles in the extracellular matrix structure and muscle regeneration. Laminin a2 -related muscular dystrophy (LGMDR23) occurs due to mutations in the LAMA2 gene, which is expressed as Laminin a2, a protein involved in myotube stability and apoptosis. POMGNT2-related muscular dystrophy (LGMDR24) occurs due to mutations in the POMGnT2 gene, protein O-linked mannose 0-1,4- N-Acetylglucosaminyl-transferase 2, which catalyzes reactions in a-dystroglycan.Compositions and formulations of neonatal cardiac mesenchymal progenitor cells (nMPCs), nMPCs secretomes, or nMPCs exosomes) for treating a dystrophinopathy or cardiomyopathy associated with a dystrophinopathy

[0064] Disclosed herein are compositions and formulations of neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome, or nMPC exosomes that can reverse or inhibit (completely or partially) pathophysiological hallmarks and symptoms of dystrophinopathy (e.g, inflammation or oxidative stress in the neurons or muscles). Alternatively, or in addition, disclosed herein are compositions and formulations of nMPC secretomes which reverse or inhibit (completely or partially) pathophysiological hallmarks and symptoms of dystrophinopathy. Alternatively, or in addition, disclosed herein are compositions and formulations of nMPC exosomes which reverse or inhibit (completely or partially) pathophysiological hallmarks and symptoms of dystrophinopathy.

[0065] nMPCs, an nMPC secretome, or nMPC exosomes can help reduce levels of inflammation, reduce levels of pro-inflammatory factors, and / or reduce levels of oxidative stress. Compositions comprising nMPCs, an nMPC secretome, or nMPC exosomes can offset the pathophysiological consequences of neurodegeneration associated with dystrophinopathy by recruiting regenerative factors and / or targeting inflammation. nMPCs, an nMPC secretome, or nMPC exosomes described herein can reduce levels of inflammation, reduce levels of pro-inflammatory factors, and / or reduce levels of oxidative stress. In some embodiments, reduction is at least 2% or more compared to a placebo or compared to a subject prior to treatment. In other embodiments, reduction is at least 2-fold or more compared to a placebo or compared to a subject prior to treatment. The goal of using the compositions comprising nMPCs, nMPC secretomes, or nMPC exosomes described herein is to offset pathophysiological consequences of degeneration of a subject by partially or treating a symptom of dystrophinopathy.

[0066] In one aspect, described herein are methods which inhibit (e.g, reduce) one or more proinflammatory cytokines including, but not limited to, Interleukin (IL)- 1(3, IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, tumor necrosis factor (TNF)-a, interferon gamma (IFN-y). In one embodiment, theWSGR Ref. No.: 64320-710.601downregulated cytokines comprise TNF-a, IL-8, MCP-1, IL-17a, and IFN-y. In another embodiment, the downregulated cytokines comprise TNF-a, IL-8, and MCP-1. In yet another embodiment, the downregulated cytokines comprise IL-17a and IFN-y. In some embodiments, the one or more proinflammatory cytokines comprise IL-8, IL-17A, MCP-1, or a combination thereof. In some embodiments, one or more anti-inflammatory cytokines in the subject are increased by at least 2% compared to treatment with a placebo or compared to the subject prior to treatment. In some embodiments, the one or more proinflammatory cytokines comprise IL-8, IL-17A, MCP-1, or a combination thereof. In one aspect, described herein are methods which promote (e.g, increase) one or more anti-inflammatory cytokines including, but not limited to, IL- 10. In some embodiments, one or more anti-inflammatory cytokines in the subject are increased by at least 2% compared to treatment with a placebo or compared to the subject prior to treatment. In some embodiments, the one or more antiinflammatory cytokines comprise IL- 10. In some embodiments, the administration of the allogeneic, human, neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (conditioned medium), nMPC exosomes, or any combination thereof, reduces levels of IL-8, IL-17A, and MCP-1, and increases levels of IL-10.

[0067] nMPCs, an nMPC secretome, or nMPC exosomes disclosed herein comprise an allogeneic, culture-expanded neonatal cardiac mesenchymal progenitor cell (nMPC) formulation with potent immunomodulatory effects and the potential to block cytokine storms. These nMPCs are isolated from the right atrial appendage of neonatal (<30 days old) donors with normal myocardium undergoing congenital heart surgery. In certain instances, therapeutic benefits of nMPCs can be exerted through their secretome, which is comprised of, for example, independently secreted growth factors, cytokines, chemokines, and / or miRNA-enriched exosomes. Robust analyses, including deep proteomic analysis and RNA sequencing of the nMPC secretome coupled with Ingenuity Pathway Analysis, have shown the presence of unique proteins and miRNA within the nMPC secretome may be responsible for downregulating fibrotic, inflammatory, and oxidative stress pathways (ERK / MAPK Signaling pathway) while promoting cellular growth, survival, and proliferation pathways. Thus, nMPCs, an nMPC secretome, or nMPC exosomes operate through a multimodal mechanism of action, enhancing pathways related to angiogenesis, immunomodulation, energy production, and cardiomyocyte proliferation while reducing oxidative stress, inflammation, and / or fibrosis.

[0068] nMPCs, an nMPC secretome, or nMPC exosomes disclosed herein have demonstrated superior therapeutic potential compared to other well -characterized and clinically relevant progenitor cell types in vitro and in vivo. The nMPCs significantly inhibited secretion of pro-inflammatory cytokines TNF-a, IL-8, and MCP-1. IL-17aand IFN-y were also shown to be reduced following exposure to nMPCs (data not shown).

[0069] In various embodiments, a damaged or dysfunctional tissue (e.g., neuronal tissue) may need repair, regeneration, or improved function due to chronic inflammation or degeneration. In some embodiments, administration of a composition as described herein comprising nMPCs, nMPCWSGR Ref. No.: 64320-710.601secretomes (conditioned medium), nMPC exosomes, or any combination thereof can result in a decrease in inflammatory factors or factors associated with oxidative stress.

[0070] The nMPCs, an nMPC secretome, or nMPC exosomes disclosed herein have demonstrated superior therapeutic potential compared to other well -characterized and clinically relevant progenitor cell types in vitro and in vivo. In an in vitro assay in which normal human dermal fibroblasts are treated with transforming growth factor beta (TGF ) in the presence or absence of the nMPC secretome, adult MPCs (aMPCs; i.e., adult counterpart of nMPCs, derived from adult right atrial appendage), bone marrow-derived MSCs (BM-MSCs), or normal human dermal fibroblasts, nMPCs’ secretome significantly can reduce expression of a fibrosis marker with superior potency compared to the other cell types.Furthermore, immunomodulatory potential of clinically relevant cell types is assessed by co-culturing cluster of differentiation (CD)4+T-cells with nMPCs, Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs), Cardiosphere-Derived Cells (CDCs), or aMPCs, and determining the proportion of CD4+, CD25+, and FoxP3+regulatory T cells (Tregs) after 5 days by flow cytometry. BM-MSCs and aMPCs fail to positively modulate the immune system while CDCs and nMPCs significantly increase Treg cell populations, with nMPCs inducing the largest increase.

[0071] In immunodeficient rats with myocardial infarction (MI), a comparative analysis was performed with five other well -characterized and clinically relevant progenitor cell types: umbilical cord blood cells, BM-MSCs, CDCs, and aMPCs. nMPCs outperformed all other cell types in improving LVEF and LV fractional shortening and in reducing cardiac fibrosis. Similarly, nMPCs were superior to other cell types in improving cardiac function post-MI in immunocompetent rats. In rat MI models, treatment with nMPCs also resulted in significantly greater reduction in the pro-inflammatory cytokines interleukin (IL)-4, IL-12, and tumor necrosis factor (TNF)-a, significantly greater upregulation of the anti-inflammatory cytokine IL- 10, and reduced macrophage infiltration in the myocardium compared to aMPCs. Thus, compared to other clinically relevant cell types, nMPCs lead to the greatest cardiac functional recovery and has the greatest anti-inflammatory, anti-fibrotic, and immunomodulatory potential.

[0072] While the initial cause of cardiac dysfunction differs, both post-MI cardiomyopathy / HF and the dilated cardiomyopathy (DCM) associated with DMD share pathological features, including cardiomyocyte death, myocardial fibrosis, mitochondrial dysfunction, oxidative stress, calcium dysregulation, and / or chronic inflammation. These lead to clinical features such as DCM, arrhythmias, and / or increased risk of cardiac death. Thus, results from post-MI animal models can provide relevant insights into the potential benefit of nMPCs in DCM associated with DMD and support evaluating the impact of nMPCs on this disease.

[0073] The multimodal mechanism of action of nMPCs, nMPC secretome, and / or nMPC exosomes, their demonstrated superiority over other tested cell types, and the observed benefits and safety profiles of other cell therapies in clinical trials for cardiomyopathy in dystrophinopathy suggest that nMPCs, nMPC secretome, and / or nMPC exosomes have the potential to address the pathophysiology and provide a therapeutic benefit to patients with cardiomyopathy in dystrophinopathy, such as, for example, DMD.WSGR Ref. No.: 64320-710.601

[0074] As used herein, “cardiomyopathy” refers to a disease of the heart muscle in which the heart muscle becomes enlarged, thick, or rigid. In rare cases, the muscle tissue in the heart is replaced with scar tissue. As cardiomyopathy worsens, the heart becomes weaker and is less able to pump blood through the body and maintain a normal electrical rhythm. This can lead to heart failure or irregular heartbeats called arrhythmias. In turn, heart failure can cause fluid to build up in the lungs, ankles, feet, legs, or abdomen. The weakening of the heart also can cause other complications, such as heart valve problems. Dilated cardiomyopathy includes left ventricle posterobasal fibrosis; conduction abnormalities are mainly intra-atrial: SVT with abnormal AV nodal conduction. Patients may further suffer from smooth muscle myopathy including vascular dysfunction, further including GI and urinary tract systems involvement. Common prognosis is death from respiratory insufficiency or cardiomyopathy. Underlying these clinical features is dystrophin gene mutation (deletion) wherein loss of dystrophin results in cellular membrane damage and leakage of extracellular Ca2+into the cell. Elevated intracellular levels ultimately result in increased oxidative and / or nitrosative stress and inflammation, and activation of calpain. The combination of these effects results in muscle proteolysis and apoptosis, leading to the degradative features described above.

[0075] In various embodiments, a damaged or dysfunctional tissue may need repair, regeneration, or improved function due to an acute event. Acute events include, but are not limited to, trauma such as laceration, crush or impact injury, shock, loss of blood or oxygen flow, infection, chemical or heat exposure, poison or venom exposure, drug overuse or overexposure, and the like. In other embodiments, the damaged tissue is cardiac tissue, and the acute event includes a myocardial infarction. In some embodiments, administration of a composition as described herein comprising nMPCs, nMPC secretome, and / or nMPC exosomes can result in an increase in cardiac wall thickness in the area subjected to the infarction.

[0076] In other embodiments, cardiac tissue is also subject to damage due to chronic disease, such as for example congestive heart failure, including as conditions secondary to diseases such as Duchenne muscular dystrophy, ischemic heart disease, hypertension, valvular heart disease, dilated cardiomyopathy, infection, diabetes, and the like.Cardiomyopathy

[0077] In some embodiments, dystrophinopathy can result in DMD-associated dilated cardiomyopathy (DCM), also known as X-linked cardiomyopathy. In one embodiment, the dystrophin gene mutation causative of DMD-associated dilated cardiomyopathy comprises Asp3368Gly, in which the 3368thamino acid residue’s asparagine is mutated to glycine. DMD-associated dilated cardiomyopathy (DCM) is a severe form of dilated cardiomyopathy caused by mutations in the DMD gene, which leads to a deficiency in the protein dystrophin. This deficiency in dystrophin results in weakened heart muscle and an increased risk of heart failure, primarily seen in individuals with Duchenne muscular dystrophy (DMD). Cardiomyopathy affects the heart muscle, changing its shape and function, causing the heart to lose its ability to pump blood well. In some cases, the heart rhythm also becomes disturbed. This leads to arrhythmias (irregular heartbeats).WSGR Ref. No.: 64320-710.601

[0078] Symptoms of cardiomyopathy in DMD patients include shortness of breath, chest pain, rapid heartbeats, and swelling in the legs, ankles, feet, stomach, and neck veins. One or more of the following tests may be recommended to diagnose cardiomyopathy. Tests include, but are not limited to, a blood test, a chest X-ray, an Electrocardiogram (EKG or ECG), a Holter and event monitor, an Echocardiogram (Echo), or a stress test. Ejection fraction is a measurement of the percentage of blood leaving the heart each time it squeezes (contracts). Ejection fraction is one of many tests a health care provider may use to see how a subject’s heart works. When the heart contracts, it pumps out (ejects) blood from the two lower heart chambers, called ventricles. When the heart relaxes, the ventricles refill with blood. No matter how forceful the contraction, the heart can never pump all the blood out of a ventricle. The term “ejection fraction” is the amount of blood (as a percentage) that's pumped out of a filled ventricle with each heartbeat. The ejection fraction is usually measured only in the left ventricle. The left ventricle is the heart's main pumping chamber. It pumps oxygen-rich blood up into the body's main artery, called the aorta, and this oxygen-rich blood then goes to the rest of the body. A left ventricle (LV) ejection fraction of about 50% to 70% is categorized as normal. A mildly reduced LV ejection fraction is usually between 41% and 49%. A reduced LV ejection fraction is usually 40% or less. Some things that may cause a reduced ejection fraction comprise weakness of the heart muscle, such as cardiomyopathy; heart attack that damaged the heart muscle; heart valve problems; and / or long-term, uncontrolled high blood pressure. Ejection fraction can be measured with imaging tests, including, but not limited to: Echocardiogram: This is the most common test used to measure ejection fraction. An echocardiogram uses sound waves to create pictures of the beating heart. It shows how blood flows through the heart and heart valves. Cardiac catheterization: A long, thin flexible tube called a catheter is inserted in a blood vessel, usually in the groin or wrist, and guided to the heart. Images taken during this test can measure the ejection fraction of a subject’s heart. Magnetic resonance imaging (MRI): An MRI uses a magnetic field and radio waves to create cross-sectional images of specific parts of the heart. Computerized tomography (CT): A CT scan uses X-rays to create cross-sectional images of specific parts of the heart. Nuclear medicine scan: During a nuclear medicine scan, trace amounts of radioactive material are put into a subject’s bloodstream through an IV. Special cameras then track the radioactive material in blood as it flows through a subject’s heart and lungs.

[0079] Confirming a diagnosis may involve one or more medical procedures. If surgery is planned, a diagnostic procedure may be performed in preparation for surgery. Such diagnostic procedures may include the following: cardiac catheterization, coronary angiography, myocardial biopsy, or genetic testing.Neonatal Cardiac Mesenchymal Progenitor Cells (nMPCs)

[0080] In one aspect, neonatal cardiac mesenchymal progenitor cells (nMPCs) for use in the methods described herein are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, andWSGR Ref. No.: 64320-710.601(d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p16INK4a. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a. In another embodiment, the nMPCs are (a) positive for protein expression of Ki67 andNkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a. In certain embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2. In some embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2. Alternatively, or in addition, the nMPCs are further negative for protein expression of p16INK4aup to at least passage 8. In some embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a. In yet other embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a

[0081] nMPCs described herein are isolated from the right atrial appendage of neonatal (<30 days old) donors with normal myocardium undergoing congenital heart surgery. The therapeutic benefits of nMPCs described herein can, in some instances, be exerted through their secretomes (conditioned media) and / or exosomes which comprise, for example, independently secreted growth factors, cytokines, chemokines, and / or miRNA. In some embodiments, the nMPCs are obtained from cardiac tissue from a neonate of less than 1 month (30 days) of age. In some embodiments, the neonatal donor is less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days old.WSGR Ref. No.: 64320-710.601

[0082] Neonatal cardiac mesenchymal progenitor cells (nMPCs) may be isolated from neonatal cardiac tissue by disaggregating tissue from the tissue of the right atrial appendage which is to serve as the source of the neonatal cardiac mesenchymal progenitor cells that are non-naturally occurring and subsequently cultured in vitro. For example, the tissue or organ can be disaggregated mechanically and / or treated with digestive enzymes and / or chelating agents that weaken the connections between neighboring cells making it possible to disperse the tissue into a suspension of individual cells without appreciable cell breakage. Enzymatic dissociation can be accomplished by mincing the tissue and treating the minced tissue with any of a number of digestive enzymes either alone or in combination. These include, but are not limited to, trypsin, chymotrypsin, collagenase, elastase, hyaluronidase, DNase, pronase, and / or dispase, etc. Mechanical disruption can also be accomplished by a number of methods including the use of grinders, blenders, sieves, homogenizers, pressure cells, sonicators, etc. In some embodiments, nMPCs are cultured under hypoxic conditions. In some embodiments, nMPCs may be cultured according to the disclosures in Example 1. The nMPCs as described and claimed herein are not naturally occurring as demonstrated by differences in the cell phenotype and secretome profile following the culture conditions.

[0083] Once the tissue has been reduced to a suspension, the suspension can be fractionated into subpopulations from which neonatal cardiac mesenchymal progenitor cells can be obtained. This also may be accomplished using techniques for cell separation including, but not limited to, cloning and selection of specific cell types, selective destruction of unwanted cells (negative selection), separation based upon differential cell agglutinability in the mixed population, freeze-thaw procedures, differential adherence properties of the cells in the mixed population, filtration, standard and zonal centrifugation, centrifugal elutriation (counter-streaming centrifugation), unit gravity separation, countercurrent distribution, electrophoresis and fluorescence-activated cell sorting (FACS).

[0084] In one embodiment, nMPCs can be substantially free of cells that have marker profiles other than those associated with nMPCs described herein. In certain embodiments, the nMPCs are at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% free of such contaminating cell types. In certain embodiments, the nMPCs are at least 80%, free of such contaminating cell types. In certain embodiments, the nMPCs are at least 85%, free of such contaminating cell types. In certain embodiments, the nMPCs are at least 90%, free of such contaminating cell types. In certain embodiments, the nMPCs are at least 95%, free of such contaminating cell types. Alternatively, or in addition, the nMPCs can also be substantially free of soluble, naturally occurring molecules. As discussed more fully below, a substantially purified progenitor cell of the disclosure can be obtained, for example, by extraction (e.g, via density gradient centrifugation and / or flow cytometry) from a culture source. Purity can be measured by any appropriate method. nMPCs described herein can be about 95%-100% purified by, for example, flow cytometry (e.g, FACS analysis), as discussed herein. Such purified nMPCs may, in certain instances, lack any retroviral DNA or retroviral RNA. In certain instances, an exemplary method of obtaining the nMPCs comprises the steps of: (a) culturing nMPCs in progenitor cell culture medium (e.g, ISTEM® from Progenitor Cells, Inc., Rooster Basal™-MSC-CC, Rooster Booster ™-MSC-CC, etc.); (b) treating the cells with a cellWSGR Ref. No.: 64320-710.601detachment solution (e.g., ACCUTASE® from Gibco # Al 1105-05, TrypLE™ Express Enzymes), and (c) collecting cells from the enzyme-treated culture to obtain the isolated nMPCs prior to one or more additional culturing methods. In some embodiments, the isolated nMPCs are allogeneic to a subject to be treated by the methods described herein.

[0085] In one embodiment, nMPCs are genetically engineered. Genetically engineering may encompass the introduction of a nucleic acid molecule (e.g, a plasmid) which encodes one or more paracrine factors. The paracrine factors may be exogenous or endogenous. In other embodiments, genetic engineering may encompass the introduction of an exogenous construct (e.g, a plasmid or an mRNA) that expresses a secreted growth factor, a cytokine, a chemokine, and / or a microRNA. In the case of an endogenous nucleic acid sequence, the nucleic acid molecule may contain a promoter and / or enhancer which induces expression or overexpression of a protein. In one non-limiting example, nMPCs are genetically engineered to express or overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In some embodiments, the nMPCs are genetically engineered to overexpress 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, andpl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPCs are: (a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2; (b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1; (c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4; and / or (e) negative for protein expression of pl6INK4aup to at least passage 8. In one embodiment, the nMPCs are: (a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2; (b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44,WSGR Ref. No.: 64320-710.601CD73, CD47, CD105, CD90, and PDL1; (c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR- 374b- 5p; and (d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a. In some embodiments, the nMPCs are further negative for protein expression of IGF 1. In some instances, the nMPCs do not express 42254. In some embodiments, the nMPCs are allogeneic or autologous. In certain embodiments, the nMPCs are non -naturally occurring. In other embodiments, the nMPCs are not xenogenic. In some embodiments, the nMPCs are obtained from a subject who is biologically a female. In certain other embodiments, the nMPCs are obtained from a subject who is biologically a male. In some embodiments, the conservative amino acid changes are made to a paracrine factor in an nMPC. In an embodiment, the conservative amino acid change improves the stability of a paracrine factor. In some embodiments, the conservative amino acid changes result in an increase in the levels of a paracrine factor. A transgene may be introduced into a neonatal cardiac mesenchymal progenitor cell via conventional techniques such as calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, electroporation, or microinjection By way of example only, a transgene may be introduced into cells using an appropriate expression vector including, but not limited to, cosmids, plasmids, or modified viruses (e.g, replication defective retroviruses, adenoviruses, and adeno-associated viruses). Transfection can be obtained by using methods including culturing the cells on a monolayer of virus-producing cells.

[0086] The disclosure also provides methods of culturing the neonatal cardiac mesenchymal progenitor cell under conditions to promote the expression of selected coding sequences. Expression includes, for example, miRNA and / or protein. In some embodiments, the coding sequence(s) can comprise a growth factor, a cytokine, a chemokine, and / or a microRNA. In one non-limiting example, the coding sequence(s) can encode HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, and / or Akt. In some embodiments, nMPCs can express a microRNA (or “miRNA”) or be genetically engineered to express the miRNA. MicroRNAs are from about 19 to about 25 nucleotides long noncoding RNAs that bind to the 3' UTR of nucleic acid molecules and downregulate gene expression either by reducing nucleic acid molecule stability or by inhibiting translation. A microRNA sequence includes a “seed” region, e.g, a sequence in the region of positions 2-8 of the mature microRNA, which sequence has Watson-Crick complementarity to the miRNA target sequence. In some embodiments, nMPCs have positive expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, miR-374b-5p, or a combination thereof. In another non-limiting example, the coding sequence(s) can encode miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In some embodiments, the cytokine may comprise an anti-inflammatory cytokine (e.g., IL-1, IL4, IL-10, IL-13, TGF-, etc.). In some embodiments, the coding sequences encoding HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p are either stably or transiently transfected into nMPCs. In one embodiment, the cells are passaged at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more times. In another embodiment, the cells are cultured for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,WSGR Ref. No.: 64320-710.60123, 24, 25, 26, 27, 28, 29, 30 or more days. In yet another embodiment, the cells are cultured in conditioned media comprising a complete medium, such as, for example, ISTEM® medium, or Rooster Basal ™- MS C-CC.

[0087] The disclosure also provides nMPCs obtained by the methods described herein. In another embodiment, the nMPCs are substantially free of any retroviral DNA or RNA (e.g, 80% or greater retroviral DNA-free or retroviral RNA-free). In another embodiment, the nMPCs are substantially free of lenti virus DNA or RNA (e.g., 80% or greater lentivirus DNA-free or lentivirus RNA-free).

[0088] In certain embodiments, nMPCs express peptides, proteins, miRNA, or a combination thereof, downregulate an inflammatory, and / or an oxidative stress pathway (ERK / MAPK signaling pathway), while promoting cellular growth, survival, and / or proliferation pathways. In some embodiments, nMPCs operate through a multimodal mechanism of action, enhancing pathways related to, for example, angiogenesis, immunomodulation, energy production, and cardiomyocyte proliferation while reducing oxidative stress and / or inflammation. In some embodiments, nMPCs can significantly reduce the expression of fibrosis markers assessed and with superior potency compared to the other cell types, such as, for example, adult MSCs (e.g, adult counterpart of nMPCs, derived from adult right atrial appendage), bone marrow- derived MSCs (BM-MSCs), or normal human dermal fibroblasts. In other embodiments, nMPCs can positively modulate the immune system by, for example, significantly increasing Treg cell populations. In some embodiments, nMPCs can downregulate cytokines. In some instances, nMPCs can downregulate inflammatory cytokines. In some embodiments, the downregulated cytokines comprise pro-inflammatory cytokines (e.g., Interleukin (IL)- 1 [3, IL-6, IL-8, IL-12, IL-17a, IL-18, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-a, interferon gamma (IFN-y)). In one embodiment, the downregulated cytokines comprise TNF-a, IL-8, MCP-1, IL-17a, and IFN-y. In another embodiment, the downregulated cytokines comprise TNF-a, IL-8, and MCP-1. In yet another embodiment, the downregulated cytokines comprise IL-17a and IFN-y. In an embodiment, nMPCs have higher immunomodulatory potential when compared to other clinically relevant cell types such as, for example, Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs), Cardiosphere-Derived Cells (CDCs), or aMPCs, as assessed by co-culturing cluster of differentiation (CD)4+T cells, and determining the proportion of CD4+, CD25+, and FoxP3+regulatory T cells (Tregs) after about 5, 6, 7, 8, 9, or 10 days by flow cytometry.

[0089] In some embodiments, the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising DMD. In some embodiments, the mutation is in a gene encoding dystrophin. In some embodiments, the dystrophin is a wild-type, human dystrophin. In some embodiments, a gene encoding a functional, wild-type, human dystrophin comprises a sequence with at least about 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 99%, or 100% identity with SEQ ID NO: 1. In some embodiments, the gene is in aXp21.2 chromosome. In some embodiments, the mutation is an out-of-frame mutation of a dystrophin gene open reading frame, and the out-of-frame mutation causes a lack of dystrophin expression.WSGR Ref. No.: 64320-710.601

[0090] In some embodiments, the nMPCs comprise a wild-type dystrophin gene encoding a functional dystrophin protein. In one embodiment, the wild-type dystrophin gene is a sequence comprising at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 99%, or 100% identity with SEQ ID NO: 1. In another embodiment, the wild-type dystrophin polypeptide or protein comprises a sequence with at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 99%, or 100% identity with SEQ ID NO: 2. In some embodiments, the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising Duchenne muscular dystrophy. In some embodiments, the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising Becker muscular dystrophy. In some embodiments, the mutation is in a gene encoding dystrophin. In one embodiment, the gene encoding dystrophin comprises a sequence with at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 99%, or 100% identity with SEQ ID NO: 1. In some embodiments, the gene is in aXp21.2 chromosome. In some embodiments, the mutation is an in-frame mutation, and the in-frame mutation causes dystrophin deficiency or dysfunction. In some embodiments, the nMPCs comprise a wild-type dystrophin gene encoding a functional dystrophin protein.

[0091] In some embodiments, nMPCs can express a microRNA (or “miRNA”). MicroRNAs are from about 19 to about 25 nucleotides long noncoding RNAs that bind to the 3' UTR of nucleic acid molecules and downregulate gene expression either by reducing nucleic acid molecule stability or by inhibiting translation. A microRNA sequence includes a “seed” region, e.g., a sequence in the region of positions 2-8 of the mature microRNA, which sequence has Watson-Crick complementarity to the miRNA target sequence.nMPC Secretomes (Conditioned Media) and Exosomes

[0092] In one aspect, provided herein are nMPC secretomes. In another aspect, provided herein are nMPC exosomes. In another aspect, provided herein is an nMPC Total Secretome comprising an nMPC secretome and nMPC exosomes. An nMPC secretome can be an nMPC Total Secretome comprising both an nMPC secretome (comprising, for example, all peptides, proteins, and nucleic acids) and nMPC exosomes. In some embodiments, an nMPC secretome or nMPC exosome as described herein is allogeneic.

[0093] An nMPC secretome (nMPC conditioned medium) can comprise nano-vesicles, microvesicles, exosomes, macromolecules such as peptides or proteins (e.g, growth factors, cytokines, etc.) and nucleic acids (e.g., miRNA, RNA, DNA), or a combination thereof. A non-limiting example of an nMPC secretome disclosed herein can comprise a chemokine, an interleukin, a growth factor, or a combination thereof. In another non-limiting example, an nMPC secretome further comprises nMPC exosomes. In certain embodiments, an nMPC secretome is isolated or purified and is not naturally occurring in a host organism or progenitor cell, from which the secretome may be derived. In some instances, the nMPC secretome is purified or extracted from a progenitor cell (e.g., an nMPC) culture or medium. In some embodiments, the nMPC secretome is non-naturally occurring or engineered. In some embodiments, an nMPC secretome can comprise a microRNA. In certain embodiments, nMPCs can be genetically modified to upregulate or downregulate a desired cellular or secretome protein or peptide. In someWSGR Ref. No.: 64320-710.601instances, the secretome may contain one or more proteins comprising a cytokine, a chemokine, a growth factor, a soluble molecule, or a combination thereof. In some instances, the one or more proteins can be separate from exosomes or microparticles. In some instances, the one or more proteins can be on the surface of exosomes or microparticles. In some instances, the one or more proteins can be encapsulated by exosomes or microparticles. In some instances, the exosomes have an average particle diameter of for example, from about 20 nm to about 250 nm in diameter or from about 50 nm to about 100 nm in diameter. In some cases, a pharmaceutical composition comprises one or more pharmaceutically acceptable excipients.

[0094] As used herein the term “exosome” refers to a small (from about 20 nm to about 300 nm in diameter, from about 50 nm to about 200 nm in diameter, or from about 50 nm to about 100 nm in diameter) nMPC vesicle comprising a membrane that encloses an internal space, and which is generated from said cell by direct plasma membrane budding or by fusion of the late endosome with the plasma membrane. The exosome is a species of extracellular vesicle. The exosome comprises lipid or fatty acid and polypeptide and optionally comprises a payload (e.g, a therapeutic agent), a receiver (e.g., a targeting moiety), a polynucleotide (e.g, a nucleic acid, miRNA, RNA, or DNA), a sugar (e.g, a simple sugar, polysaccharide, or glycan) or other molecules. The exosome is an nMPC exosome, and isolated from the nMPCs based on its size, density, biochemical parameters, or a combination thereof. Exosomes generally contain a lipid bilayer with a center containing fluid, DNA, RNA, miRNAs, peptides, and / or proteins. The bilayer comprises lipids including, but not limited to, cholesterol, a diglyceride, a ceramide, a sphingolipid (e.g., sphingomyelin, ceramide, etc.), a phospholipid, a glycerophospholipid (such as, for example, phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and polyglycerophospholipids (e.g., bisphosphate)), gangliosides (GM), or a combination thereof. The nMPC exosomes can also comprise a transmembrane protein, tetraspanin, antigen presenting molecule, glycoprotein, adhesion molecule, heat shock protein (Hsp), cytoskeletal protein, ESCRT component, membrane transport protein, fusion protein, growth factor, cytokine, lipid, fas ligand (FasL), mRNA, miRNA, non-coding RNA, DNA, TNF receptor, or transferrin receptor (TfR), or a combination thereof.

[0095] As used herein, the term “extracellular vesicle” or “EV” refers to a cell -derived vesicle comprising a membrane that encloses an internal space. Extracellular vesicles comprise all membranebound vesicles that have a smaller diameter than the cell from which they are derived. Generally, extracellular vesicles can range in diameter from about 20 nm to about 1000 nm and can comprise various macromolecular payload either within the internal space, displayed on the external surface of the extracellular vesicle, and / or spanning the membrane. In certain embodiments, extracellular vesicles range in diameter from about 50 nm to about 200 nm and can comprise various macromolecular payloads either within the internal space, displayed on the external surface of the extracellular vesicle, and / or spanning the membrane. Said payload can comprise nucleic acids (e.g., DNA, RNA, miRNA, etc.), peptides, proteins, carbohydrates, lipids, small molecules, and / or combinations thereof. RNA can comprise, for example, miRNAs, messenger mRNA (mRNA), circular RNA (circRNA), IncRNA (long non-codingWSGR Ref. No.: 64320-710.601RNA), etc. By way of example and without limitation, extracellular vesicles include apoptotic bodies, fragments of cells, vesicles derived from cells by direct or indirect manipulation (e.g, by serial extrusion or treatment with alkaline solutions), vesiculated organelles, and vesicles produced by living cells (e.g, by direct plasma membrane budding or fusion of the late endosome with the plasma membrane). Extracellular vesicles can be derived from a living or dead organism, explanted tissues or organs, and / or cultured cells. In some embodiments, an nMPC exosome, as described herein, is allogeneic.

[0096] In certain embodiments, an nMPC secretome comprises peptides, proteins, miRNA, or a combination thereof, responsible for downregulating a fibrotic, inflammatory, and / or oxidative stress pathway (ERK / MAPK signaling pathway), while promoting cellular growth, survival, and / or proliferation pathways. In some embodiments, an nMPC secretome operates through a multimodal mechanism of action, enhancing pathways related to, for example, angiogenesis, immunomodulation, energy production, and cardiomyocyte proliferation while reducing oxidative stress, inflammation, and / or fibrosis. In some embodiments, an nMPC secretome can significantly reduce the expression of fibrosis markers assessed and with superior potency compared to the other cell types, such as, for example, adult MSCs (e.g, adult counterpart of nMPCs, derived from an adult right atrial appendage), bone marrow-derived MSCs (BM-MSCs), or normal human dermal fibroblasts. In other embodiments, an nMPC secretome can positively modulate the immune system by, for example, significantly increasing Treg cell population. In some embodiments, an nMPC secretome downregulates cytokines. In some embodiments, the downregulated cytokines comprise pro-inflammatory cytokines (e.g, Interleukin (IL)- 1 [3, IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, tumor necrosis factor (TNF)-a, interferon gamma (IFN-y)). In one embodiment, the downregulated cytokines comprise TNF-a, IL-8, MCP-1, IL-17a, and IFN-y. In another embodiment, the downregulated cytokines comprise TNF-a, IL-8, and MCP-1. In yet another embodiment, the downregulated cytokines comprise IL- 17a and IFN-y. In an embodiment, an nMPC secretome has higher immunomodulatory potential when compared to other clinically relevant cell types such as, for example, Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs), Cardiosphere-Derived Cells (CDCs), or aMPCs, as assessed by co-culturing cluster of differentiation (CD)4+T cells, and determining the proportion of CD4+, CD25+, and FoxP3+regulatory T cells (Tregs) after about 5, 6, 7, 8, 9, or 10 days by flow cytometry.

[0097] In one embodiment, the nMPC secretome or the nMPC exosome is isolated. In certain embodiments, the nMPC secretomes and / or nMPC exosomes are at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% free of cells. In one embodiment, the nMPC secretomes and / or nMPC exosomes are at least about 90% free of cells. In another embodiment, the nMPC secretomes and / or nMPC exosomes are at least about 95% free of cells. In one embodiment, the nMPC secretomes and / or nMPC exosomes are at least about 99% free of cells. In yet another embodiment, the nMPC secretomes and / or nMPC exosomes are at least about 99.5% free of cells.

[0098] Substantially purified nMPCs, nMPC secretome, and / or nMPC exosomes described herein can be obtained, for example, by extraction (e.g, via density gradient centrifugation and / or flow cytometry)WSGR Ref. No.: 64320-710.601and filtration (e.g., size exclusion chromatography) from a culture source. Purity can be measured by any appropriate method.

[0099] A neonatal cardiac mesenchymal progenitor stem cell secretome and / or exosome of the disclosure can be about 99%-100% purified by, for example, size exclusion chromatography, as discussed herein. Such purified nMPC secretomes and / or nMPC exosomes may also lack any retroviral DNA or retroviral RNA. In certain instances, the method of obtaining the nMPC secretomes and / or exosomes comprise the steps of: (a) culturing nMPCs in progenitor cell culture medium (e.g, ISTEM® from Progenitor Cells, Inc., Rooster Basal™-MSC-CC, Rooster Booster™-MSC-CC, etc.); (b) treating the cells with a cell detachment solution (e.g., ACCUTASE® from Gibco # Al 1105-05, TrypLE™ Express Enzymes), (c) centrifuging the cultures by standard or ultracentrifugation, (d) collecting the supernatant, and optionally (e) using size exclusion chromatography. In some embodiments, an isolated or purified secretome and / or exosome as described herein is allogeneic. In one aspect, disclosed herein is a composition that comprises a secretome, e. g., a protein, an exosome, or a microvesicle secreted from a cell or cells (e.g, neonatal cardiac mesenchymal progenitor cells).

[0100] In some embodiments, an nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. In another embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPC secretome is positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p.

[0101] In some embodiments, the nMPC exosomes are positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPC exosomes are positive for protein expression of CD81 and / or CD63. In some embodiments, the nMPC exosomes are positive for protein expression of CD81 and CD63.

[0102] In some embodiments, an nMPC is genetically modified to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, or Akt such that the level of each overexpressed factor is greater in the isolated nMPC secretome and / or nMPC exosomes as compared to the level of each factor in a secretome or exosomes isolated from nMPCs that have not been genetically modified. In some embodiments, an nMPC is genetically modified to overexpress miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p such that the level of each overexpressed miRNA is greaterWSGR Ref. No.: 64320-710.601in the isolated nMPC secretome and / or nMPC exosomes as compared to the level of each miRNA in a secretome isolated from nMPCs that have not been genetically modified.

[0103] In other embodiments, the nMPC secretome and / or nMPC exosomes have a marker (e.g., protein) expression profile as provided in Table 7. In some embodiments, an nMPC secretome and / or nMPC exosomes are negative for protein expression of IGF 1. In other embodiments, nMPCs are genetically engineered to overexpress one or more paracrine factors. In other embodiments, nMPCs are genetically engineered to overexpress one or more markers (e.g, proteins) provided in Table 7. In certain embodiments, nMPCs can be genetically modified to upregulate or downregulate a desired cellular or exosomal protein or peptide that can be detected in the secretome by conventional means. In some embodiments, the nMPC secretome and / or nMPC exosomes are produced by culturing nMPCs cells for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days and collecting the supernatant of the cultured cells. In some embodiments, the nMPC secretome and / or nMPC exosomes are concentrated.

[0104] The nMPC exosomes can be characterized by their particle size. In some embodiments, an exosome described herein can comprise a particle in a range of from about 50 nm to about 100 nm, from about 50 nm to about 190 nm, from about 50 nm to about 180 nm, from about 50 nm to about 170 nm, from about 50 nm to about 160 nm, from about 50 nm to about 150 nm, from about 50 nm to about 140 nm, from about 50 nm to about 130 nm, from about 50 nm to about 120 nm, from about 50 nm to about 110 nm, from about 50 nm to about 100 nm, from about 50 nm to about 90 nm, from about 50 nm to about 80 nm, from about 50 nm to about 70 nm, or from about 50 nm to about 60 nm in diameter. In an embodiment, an exosome described herein can comprise a particle from about 50 nm to about 90 nm in diameter. In an embodiment, an exosome described herein can comprise a particle from about 50 nm to about 100 nm in diameter. In an embodiment, an exosome described herein can comprise a particle from about 50 nm to about 110 nm in diameter. The nMPC exosomes described herein can comprise particles in a range of from about 50 nm to about 1000 nm, about 100 nm to about 1000 nm, about 500 nm to about 1000 nm, about 600 nm to about 900 nm, about 700 nm to about 800 nm, about 300 nm to about 600 nm, about 300 nm to about 500 nm, 300 nm to about 400 nm, about 200 nm to about 500 nm, 200 nm to about 400 nm, about 100 nm to about 500 nm, about 100 nm to about 300 nm, 100 nm to about 200 nm, 100 nm to about 150 nm, about 50 nm to about 200 nm, about 50 nm to about 150 nm, about 50 nm to about 110 nm, about 50 nm to about 100 nm, about 75 nm to about 250 nm, about 75 nm to about 200 nm, about 75 nm to about 150 nm, about 75 nm to about 100 nm, about 90 nm to about 150 nm, about 90 nm to about 125 nm, about 90 nm to about 110 nm, or about 90 nm to about 100 nm in diameter. In one embodiment, the nMPC exosomes comprise particles in a range of from about 90 nm to about 110 nm in diameter. In another embodiment, the nMPC exosomes comprise particles in a range of from about 100 nm to about 120 nm in diameter. In some embodiments, the nMPC exosomes comprise particles about 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, or 1000 nm in diameter. In someWSGR Ref. No.: 64320-710.601embodiments, the nMPC exosomes comprise particles about 90 nm in diameter. In certain embodiments, the nMPC exosomes comprise particles about 100 nm in diameter. In other embodiments, the nMPC exosomes comprise particles about 110 nm in diameter. In yet other embodiments, the nMPC exosomes have a density of about 1.13 g / ml to about 1.19 g / ml.Compositions and Formulations

[0105] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with one or more pharmaceutically acceptable excipients to be administered to a subject, e.g, a human in need thereof. A pharmaceutical composition used in the therapeutic methods of the invention is formulated to be compatible with its intended route of administration. In certain embodiments, the active pharmaceutical ingredient comprises, for example, neonatal cardiac mesenchymal progenitor cells, nMPC secretomes (nMPC conditioned media), nMPC exosomes, or any combination thereof. In some embodiments, the pharmaceutical formulation comprises nMPCs only in a pharmaceutically acceptable carrier (e.g., phosphate buffered saline). In some embodiments, the pharmaceutical formulation comprises nMPCs and their secretome (e.g., conditioned media) in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation comprises nMPC secretome (e. g., conditioned media) in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation comprises nMPC exosomes only in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation comprises nMPCs, nMPCs, nMPC secretome (comprising, for example, peptides or proteins (e.g., cytokines, growth factors, etc.), nucleic acids (e.g, miRNA, RNA, DNA), or any combination thereof), and / or nMPC exosomes. In one embodiment, the pharmaceutical formulation comprises nMPCs, nMPC secretome, and / or nMPC exosomes, in a pharmaceutically acceptable carrier.Protein Concentrations

[0106] The compositions described herein can comprise the nMPC secretome and / or nMPC exosomes at a final protein concentration. A final protein concentration can be adjusted to achieve therapeutic efficacy depending on measured symptoms of a subject by a clinician. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of from about 0.1 mg / ml to about 50.0 mg / ml, or from about 0.5 mg / ml to about 20.0 mg / ml. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of (a) at least about 0.1 mg / ml, 0.5 mg / ml, 1.0 mg / ml, about 2.0 mg / ml, about 3.0mg / ml, about 4.0 mg / ml, about 5.0 mg / ml, about 6.0 mg / ml, about 7.0 mg / ml, about 8.0 mg / ml, about 9.0 mg / ml, about 10.0 mg / ml, about 11.0 mg / ml, about 12.0 mg / ml, about 13.0 mg / ml, about 14.0 mg / ml, about 15.0 mg / ml, about 16.0 mg / ml, about 17.0 mg / ml, about 18.0 mg / ml, about 19.0 mg / ml, about 20.0 mg / ml, about 22.0 mg / ml, about 24.0 mg / ml, about 26.0 mg / ml, about 28.0 mg / ml, about 30.0 mg / ml, about 35.0 mg / ml, about 40.0 mg / ml, about 45.0 mg / ml, or about 50.0 mg / ml, or (b) at most about 250.0 mg / ml, about 225.0 mg / ml, about 200.0 mg / ml, about 175 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 75 mg / ml, about 50 mg / ml, about 45.0 mg / ml, about 40.0 mg / ml, about 35.0 mg / ml, about 30.0 mg / ml, about 25 mg / ml,WSGR Ref. No.: 64320-710.601about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, about 1 mg / ml, about 0.5 mg / ml, or about 0.1 mg / ml. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 1.0 mg / ml ±0.1, ±0.2, ±0.3, ±0.4, or ±0.5. In other embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 4.0 mg / ml ±0.5, ±1.0, ±1.5, ±2.0, ±2.5, or ±3.0. In some embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 8.0 mg / ml ±1.0, ±2.0, ±3.0, ±4.0, or ±5.0. In certain embodiments, the nMPC secretome and / or nMPC exosomes comprise a final protein concentration of at least about 16.0 mg / ml ±2.0, ±3.0, ±4.0, ±5.0, or ±6.0.Combination Therapy

[0107] In some embodiments, a pharmaceutical formulation disclosed herein is administered in combination with a drug or therapeutic agent. In certain aspects, combination therapy is contemplated wherein the nMPCs, nMPC secretome, and / or nMPC exosomes are administered with a drug or a therapeutic agent. For example, in some embodiments, the drug or therapeutic agent comprises aldosterone antagonist, an angiotensin-converting enzyme inhibitor (ACEi), an angiotensin receptor blocker (ARB), a beta blocker, a blood thinner, a cardiac glycoside, a diuretic, a biguanide, a statin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a glucagon- 1 receptor agonist, a corticosteroid, an exon-skipping therapy, an AAV-based gene therapy, a HD AC inhibitor, or any combination thereof. In some embodiments, the one or more other therapeutic agents help to relieve one or more symptoms of cardiomyopathy or DMD. Aldosterone antagonists include, but are not limited to, Carospir, Eplerenone, or Spironolactone. Angiotensin- converting enzyme inhibitors (ACEi) include, but are not limited to, Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, or Trandolapril. Angiotensin receptor blockers (ARB) include, but are not limited to, Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, or Valsartan. Beta-blockers include, but are not limited to, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol, Labetalol, Metoprolol, Nadolol, Nebivolol, Penbutolol, Pindolol, Propanolol, Sotalol, or Timolol. Blood thinners include, but are not limited to, Apixaban, Dabigatran, Dalteparin, Edoxaban, Enoxaparin, Fondaparinux, Heparin, Rivaroxaban, or Warfarin. Cardiac glycosides include, but are not limited to, Digoxin. Diuretics can comprise Bumetanide, Chlorthalidone, Chlorothiazide, Ethacrynate, Furosemide, Hydrochlorothiazide HCTZ, Indapamide, Methyclothiazide, Metolazone, or Torsemide. Biguanides include, but are not limited to, Metformin. Statins include, but are not limited to, Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, or Simvastatin. Sodium-glucose Cotransporter-2 (SGLT2) inhibitors include, but are not limited to, Canagliflozin, Dapagliflozin, Empagliflozin, or Ertugliflozin. Glucagon- 1 receptor agonists include, but are not limited to, Dulaglutide, Exenatide, Exenatide Extended Release, Liraglutide, Lixisenatide, Semaglutide subcutaneous (tablet), or Tirzepatide. Corticosteroids include, but are not limited to, Prednisone, Deflazacort, or Vamorolone. Exon-skipping therapies include, but are not limited to, Eteplirsen (for exon 51 skipping), Golodirsen (for exon 53 skipping), Viltolarsen (for exon 53 skipping), Casimersen (for exon 45 skipping). AAV-based gene therapy includes, but is not limited to,WSGR Ref. No.: 64320-710.601Elevidys. HD AC inhibitors include, but are not limited to, Givinostat. In other embodiments, the drug or therapeutic agent comprises a medication from Table 2A.Table 2A. Combination medications for the treatment of DCMClass MedicationsAldosterone antagonists Carospir, Eplerenone, Spironolactone, OtherAngiotensin- converting enzyme Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, inhibitors (ACEi) Perindopril, Quinapril, Ramipril, Trandolapril, Other Angiotensin receptor blockers (ARB) Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan, OtherAcebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol, Beta blockers Labetalol, Metoprolol, Nadolol, Nebivolol, Penbutolol, Pindolol,Propanolol, Sotalol, Timolol, OtherApixaban, Dabigatran, Dalteparin, Edoxaban, Enoxaparin, Blood thinners Fondaparinux, Heparin, Rivaroxaban, Warfarin, Other Cardiac glycosides DigoxinBumetanide, Chlorthalidone, Chlorothiazide, Ethacrynate, Diuretics Furosemide, Hydrochlorothiazide HCTZ, Indapamide,Methyclothiazide, Metolazone, Torsemide, Other Biguanides MetforminStatins Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, Simvastatin Sodium- glucose Cotransporter-2 Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Other (SGLT2) inhibitorsDulaglutide, Exenatide, Exenatide Extended Release, Liraglutide, Glucagon- 1 receptor agonists Lixisenatide, Semaglutide subcutaneous (tablet), Tirzepatide,Other0108] In other embodiments, the method includes combination therapy with one or more additional medications, for example, those listed in Table 2B. Medications for the treatment of DMD should be taken as clinically indicated and prescribed by the physician. Any changes to medications directed towards the treatment of the myopathy in DMD are recorded. These medications may include, but are not limited to, the approved drugs in Table 2B.Table 2B. Medications Approved for Combination TherapyType MedicationsCorticosteroids Prednisone, Deflazacort, VamoroloneEteplirsen (for exon 51 skipping), Golodirsen (for exon 53 Exon-skipping therapies skipping), Viltolarsen (for exon 53 skipping), Casimersen (for exon 45 skipping)AAV-based gene therapy ElevidysHD AC Inhibitors Givinostat

[0109] nMPC Efficacy In-Line with Efficacy of GLP-1 AgonistsWSGR Ref. No.: 64320-710.601

[0110] nMPCs can improve KCCQ and 6MWT results on par with incretins and more than SGLT2 inhibitors. Incretins are gut hormones that increase insulin secretion after a meal, while SGLT2 inhibitors are medications that work by blocking the kidneys’ ability to reabsorb sugar, causing it to be excreted in urine. SGLT2 inhibitors facilitate the removal of glucose through the urine to lower blood sugar levels. In some embodiments, nMPCs, nMPC secretome, nMPC exosomes, an nMPC total secretome, or a combination thereof, can improve KCCQ and 6MWT by 2% or more, or by 2-fold or more, following treatment as compared to treatment with a standard of care.

[0111] For intravenous or intramyocardial infusion administration, suitable carriers include, but are not limited to, physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N. J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It can be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0112] The separate components of the compositions or formulations disclosed herein may be preblended or each component may be added separately to the same environment according to a predetermined dosage for the purpose of achieving the desired concentration level of the treatment components and so long as the components eventually come into intimate admixture with each other. Further, the compositions or formulations disclosed herein may be administered or delivered on a continuous or intermittent basis. In some embodiments, nMPC secretomes and / or nMPC exosomes may be separately produced, isolated, and concentrated, followed by the blending or titration of a specific number or concentration of nMPCs into a volume of the composition or formulation comprising nMPC secretomes and / or nMPC exosomes. In certain embodiments, nMPCs may be administered at a final concentration of at least about 1 xlO6, 2*106, 3*106, 4X106, 5*106, 6*106, 7xl06, 8xl06, 9xl06, 10xl06, 15xl06, 20xl06, 25xl06, 30xl06, 35xl06, 40xl06, 45xl06, 50xl06, 55xl06, 60xl06, 65xl06, 70xl06, 75xl06, 80xl06, 85xl06, 90xl06, 95xl06, lOOxlO6, HOxlO6, 120xl06, 130xl06, 140xl06, 150xl06, 160xl06, 170xl06, 180xl06, 190xl06, 200xl06, 210xl06, 220xl06, 230xl06, 240xl06, or 250xl06neonatal cardiac mesenchymal progenitor cells. In some embodiments, each dose comprises from about 20-50xl06, about 30-80xl06, about 50-100xl06, about 80-120xl06, about 110-150xl06, about 140-180xl06, about 150-200xl06, or about 190-250xl06neonatal cardiac mesenchymal progenitor cells. In certain embodiments, each dose of the nMPCs comprises from about 15 million to about 250 million nMPCs. In some embodiments, each dose of the nMPCs comprises from about 35 million to about 65 million nMPCs. In some embodiments, each dose of the nMPCs comprises from about 45 million to about 55 million nMPCs. In a non-limiting example, a dose of the nMPCs comprises about 50 million nMPCs. In another non-limiting example, a dose of the nMPCs comprises from about 85 million to about 115 million nMPCs. In yet another non-limiting example, a dose of the nMPCs comprises from about 95 million to about 105 million nMPCs. In anon-limiting example, a dose of the nMPCs comprises about 100 million nMPCs. In a non-limiting example, a dose of the nMPCs comprises from about 135 million to about 165 million nMPCs. In another non-limiting example, a dose of the nMPCs comprises from about 145 million to about 155 million nMPCs. In anon-limiting example, a dose of the nMPCsWSGR Ref. No.: 64320-710.601comprises about 150 million nMPCs. In yet another non-limiting example, a dose of the nMPCs comprises from about 185 million to about 215 million nMPCs. In anon-limiting example, a dose of the nMPCs comprises from about 195 million to about 200 million nMPCs. In an embodiment, a dose of the nMPCs comprises about 200 million nMPCs. In another non-limiting example, a dose of the nMPCs comprises from about 235 million to about 265 million nMPCs. In anon-limiting example, a dose of the nMPCs comprises from about 245 million to about 255 million nMPCs. In anon-limiting example, a dose of the nMPCs comprises about 250 million nMPCs. In some embodiments, each dose comprises about 50* 106, about 100*106, or about 200 / IO6nMPCs. In some embodiments, each starting dose comprises about 50* 106, about 100* 106, or about 200 *106nMPCs. In an embodiment, a starting dose comprises about 50 / IO6nMPCs. In another embodiment, a starting dose comprises about 100x106nMPCs. In another embodiment, a starting dose comprises about 200 / IO6nMPCs. In yet another embodiment, a starting dose comprises about 240 / IO6nMPCs.

[0113] In some embodiments, provided herein are pharmaceutical compositions and methods of producing the pharmaceutical formulations. In any of such embodiments, nMPCs, an nMPC secretome, nMPC exosomes, or a combination thereof, may be introduced into a volume appropriate for intravenous infusion; for example, in an amount of about 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000 ml, etc. In the compositions disclosed herein, each dose comprising nMPCs, an nMPC secretome, nMPC exosomes, or a combination thereof, comprises a volume of about a liter or less, about 500 ml or less, about 250 ml or less, or about 100 ml or less. In some embodiments, compositions or formulations comprising nMPCs, an nMPC secretome, nMPC exosomes, or a combination thereof, the compositions or formulations comprise a volume of a liter or less, about 500 ml or less, about 250 ml or less, or about 100 ml or less for each dose. In certain embodiments, a composition or formulation as disclosed herein is manufactured in accordance with Good Manufacturing Practices (GMP), a set of quality assurance standards for the production of medicinal products.Storage Conditions

[0114] In any of such methods, the nMPCs are stable in storage at a temperature for a period of time. In some embodiments, the temperature is about 4 °C, 1 °C, 0 °C, -10 °C, -20 °C, or -80 °C. In some embodiments, the period of time is at least about 1, 2, 3, 4, 5, 6, or 7 days; at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks; or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months. In some embodiments, the nMPCs are stored in cell cryopreservation media-CS10 (CRYOSTOR®; Sigma- Aldrich, Israel). In some embodiments, the nMPCs are thawed in a 37 °C water bath until a single ice crystal remained prior to administration to the subject. In some embodiments, the nMPCs are further washed with a volume of Complete Medium (CM). In some embodiments, the nMPCs are washed twice with a volume of Complete Medium (CM). In some embodiments, the volume is at least about 10 ml.WSGR Ref. No.: 64320-710.601Protein Expression Detection

[0115] Assessment of the presence or levels of protein expression of the one or more factors (e.g, c-kit (CD117), HSF1, Ki67, CD44, CD73, CD47, CD105, CD90, Nkx2.5, CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and / or SSEA4, etc.) can be performed by, for example, detection of a signal (e.g, signal produced by a fluorescent protein) using FACS, or selection by another marker such as an antibiotic resistance marker. In some cases, the signal used to assess presence or levels of protein expression was produced by a fluorescently labeled antibody (e.g., an antibody labeled with FITC, phycoerythrin (PE), Peridinin-Chlorophyll-protein (PerCP), or Allophycocyanin (APC)) that could bind to a factor. In some cases, the presence or levels of protein expression of the one or more factors was measured by antibody staining, fluorescence microscopy, flow cytometry as discussed above, protein labeling, an enzyme-linked immunosorbent assay (ELISA), mass spectroscopy, western blotting, or Bradford protein assays. Such assays can be used to evaluate the level of expression of a factor: for example, higher protein expression levels may be correlated with stronger signals (e.g, fluorescent signals), and lower expression levels may be correlated with weaker signals. The cells may be separated based on the level of staining for a particular antigen or lack thereof. Expression levels are compared to a positive control and / or a negative control.RNA Sequencing

[0116] High-throughput RNA sequencing (RNA-Seq) technology, enabled by the developments in nextgeneration sequencing, represents a powerful tool in analyzing gene expression profdes, detecting transcript variants, and understanding the function of the non-coding regulatory RNAs. An RNA-Seq library can be generated from ligating sequencing adapters to double-stranded DNA. A first RNA-Seq library method of generating a comprises ligating different adapters to the 3' and 5' ends of the RNA molecules (see, e.g, Ion Total RNA-Seq Kit v2 from Life Technologies). A second method comprises incorporating dUTP in addition to dNTPs in the second strand DNA synthesis. Following adapter ligation, the second strand DNA can be specifically digested by an Uracil -N-glycosylase (UNG) enzyme so that only the library strand containing the first strand cDNA will be sequenced and information on the direction of the transcripts can therefore be obtained (see, M. Sultan et al., Biochemical and Biophysical Research Communications, 422 (2012) 643-646). A third method uses the techniques described in, for example, U. S. Pat. No. 11248262B2 in which a method of RNA sequencing comprises: (i) providing RNA; (ii) generating (a) single-stranded first DNA strand(s) (cDNA), which is / are complementary to the RNA, by subjecting the RNA to reverse transcription by using a reverse transcriptase, a first set of oligonucleotide primers, and the RNA of step (i), and (iii) generating a second DNA strand by using a DNA polymerase, a second set of oligonucleotide primers, and the single-stranded cDNA of (ii), wherein a) the first set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated first DNA strand; or b) the second set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated second DNA strand. In certain instances, the method further comprises the subsequent steps of: (iv) optionally end-repairing the double-stranded DNAWSGR Ref. No.: 64320-710.601strands using a polynucleotide kinase and an enzyme with polymerase and exonuclease activities to obtain end-repaired DNA strands; (v) optionally adding a terminal adenine to the 3' termini of the DNA strands using a deoxynucleotidyl transferase enzyme; and (vi) ligation of adapters, which optionally comprise terminal thymines, to the DNA strands, which optionally comprise 3' terminal adenines. The methods may further comprise sequence analysis of the generated DNA.

[0117] In some embodiments, said method comprises: (i) providing RNA; (ii) generating (a) singlestranded first DNA strand(s) (cDNA), which is / are complementary to the RNA, by subjecting the RNA to reverse transcription by using a reverse transcriptase, a first set of oligonucleotide primers, and the RNA of step (i); (iii) generating a second DNA strand by using a DNA polymerase, a second set of oligonucleotide primers, and the single-stranded cDNA of (ii); (iv) ligating adapters to the doublestranded DNA; of step (iii) and (v) sequencing the generated DNA, wherein a) the first set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated first DNA strand; or b) the second set of oligonucleotide primers comprises a covalently coupled moiety at its / their 5' terminal nucleotide, which blocks ligation at the 5' terminus of the generated second DNA strand. By generating the second DNA strand, a double-stranded DNA is generated.

[0118] In some embodiments, of the above-mentioned method, prior to step (iv), the method comprises the step of: (iii)(a) end-repairing the double-stranded DNA strands using a polynucleotide kinase and an enzyme with polymerase and exonuclease activities to obtain end-repaired DNA strands.

[0119] In some embodiments, step (iii)(a) is followed by step (iii)(b) comprising adding a terminal adenine to the 3' termini of the DNA strands by using a deoxynucleotidyl transferase enzyme, wherein the adapters comprise 3' terminal thymines, which in step (iv) ligate to the DNA strands comprising 3' terminal adenines. In some embodiments, the oligonucleotide primers, which are covalently coupled to a blocking moiety and / or unmodified oligonucleotide primers, are random oligonucleotide primers.

[0120] In some embodiments, said methods comprise the initial step of extracting and optionally enriching the RNA of interest. In some embodiments, the extracted RNA is fragmented to an average size of from about 19 to about 510 bp. In some embodiments, of the above methods, the molecules may be attached to a solid support for paired-end sequencing.Methods of Treatment

[0121] The neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome, and / or nMPC exosomes as provided herein can used to reduce the likelihood or severity of, inhibit, or treat a dystrophinopathy in a subject in need thereof. The neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome, and / or nMPC exosomes as provided herein can used to reduce the likelihood or severity of, inhibit, or treat one or more symptoms of dystrophinopathy in a subject in need thereof.

[0122] Subjects to be treated by the methods described herein are diagnosed as having a dystrophinopathy. In some embodiments, the dystrophinopathy comprises Duchenne muscular dystrophy (DMD). In some other embodiments, the dystrophinopathy comprises Becker muscular dystrophyWSGR Ref. No.: 64320-710.601(BMD). In certain embodiments, the method comprises treating cardiomyopathy in a subject diagnosed with Duchenne muscular dystrophy (DMD). In certain other embodiments, the method comprises treating cardiomyopathy in a subject diagnosed with Becker muscular dystrophy (BMD). In some embodiments, the method comprises treating DMD-associated dilated cardiomyopathy (DCM), also known as X-linked cardiomyopathy. In some embodiments, the dystrophinopathy comprises an Emery -Dreifuss muscular dystrophy. In some embodiments, the dystrophinopathy comprises a myotonic muscular dystrophy. In some embodiments, the dystrophinopathy comprises a facioscapulohumeral muscular dystrophy (FSMD). In some embodiments, the dystrophinopathy comprises a congenital muscular dystrophy. In some embodiments, the dystrophinopathy comprises a limb-girdle muscular dystrophy (LGMD). In some embodiments, the dystrophinopathy comprises an oculopharyngeal muscular dystrophy. In some embodiments, the dystrophinopathy comprises a congenital muscular dystrophy. In some embodiments, the dystrophinopathy comprises a congenital myopathy. In some embodiments, the dystrophinopathy comprises a myofibrillar myopathy. In some embodiments, the dystrophinopathy comprises an inclusion body myositis (IBM). In some embodiments, the dystrophinopathy comprises a myotonic dystrophy. In some embodiments, the dystrophinopathy comprises a metabolic myopathy. In some embodiments, the dystrophinopathy comprises a mitochondrial myopathy. In some embodiments, the dystrophinopathy comprises an inflammatory myopathy. In some instances, compositions comprising nMPCs, an nMPC secretome, and / or nMPC exosomes can be administered to asymptomatic carriers of a mutation known to be causative of dystrophinopathy. Diagnosis can be measured through a comprehensive evaluation by a medical professional, including, for example, a physical evaluation, medical history review, and one or more diagnostic tests. In certain embodiments, the one or more diagnostic tests comprise(s) genetic testing (e.g., DMD gene deletion-duplication analysis, Sanger DNA sequencing, Next-generation DNA sequencing, RNA sequencing, etc.), immunohistochemical analyses (e.g, analysis of muscle biopsy cryosections, immunoblots), biochemical analyses (e.g, protein truncation tests, PCR, etc.), and / or blood tests (e.g, detection of elevated CKlevels, etc.). In one aspect, the subject treated by the method exhibits an improvement of one or more symptoms of cardiomyopathy by about 2% or more compared to treatment with a placebo or compared to the subject prior to administration of the nMPCs, an nMPC secretome, nMPC exosomes, or an nMPC Total Secretome. In any of such methods, the nMPCs are allogeneic. In any of such methods, the subject to be treated can be a mammal such as, for example, a human. The human can be a child (from birth to 18 years of age) or an adult (over 18 years of age). In some embodiments, the subject to be treated is from about 4 years of age to about 30 years of age. In some embodiments, the subject to be treated is from about 4 years of age to about 18 years of age. In some embodiments, the subject to be treated is from about 18 years of age to about 30 years of age. In some embodiments, the subject to be treated has received a diagnosis of dilated cardiomyopathy (DCM). In certain embodiments, the method comprises treating cardiomyopathy in a subject diagnosed with a dystrophinopathy and dilated cardiomyopathy.

[0123] In some embodiments, compositions comprising nMPCs, an nMPC secretome, and / or nMPC exosomes can be administered to a carrier of a mutation known to be causative of dystrophinopathy. InWSGR Ref. No.: 64320-710.601some embodiments, the mutation is in a gene encoding dystrophin. In some embodiments, the gene is in a Xp21.2 chromosome. In some embodiments, the mutation is in a dystrophin polypeptide or dystrophin protein. In some embodiments, the mutation is in a gene comprising a sequence with at least about 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 99%, or 100% identity with SEQ ID NO: 1. In another embodiment, the mutation is in a dystrophin polypeptide or dystrophin protein comprising a sequence with at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 99%, or 100% identity with SEQ ID NO: 2

[0124] The nMPCs, nMPC secretome, and / or nMPC exosomes as provided herein can also produce clinically relevant effects such as the potential to block cytokine storms to reduce inflammation. nMPCs’ expression of unique proteins and miRNA can downregulate fibrotic, inflammatory, and oxidative stress pathways (ERK / MAPK Signaling pathway) while promoting cellular growth, survival, and proliferation pathways. Pathways related to angiogenesis, immunomodulation, energy production, and cardiomyocyte proliferation while reducing oxidative stress, inflammation, and fibrosis are improved by nMPCs.

[0125] Subjects to be treated can be from about 4 to about 18 years of age, from about 4 to about 30 years of age, from about 18 to about 30 years of age, from about 19 to about 25 years of age, or 26 years of age or older. In some embodiments, the subject to be treated is from about 4 to about 30 years of age. In some embodiments, the subject to be treated is from about 4 to about 18 years of age. In some embodiments, the subject to be treated is from about 18 to about 30 years of age. In one embodiment, the subject to be treated is about 4 years of age. In another embodiment, the subject to be treated is about 5 years of age. In another embodiment, the subject to be treated is about 6 years of age. In another embodiment, the subject to be treated is about 7 years of age. In another embodiment, the subject to be treated is about 8 years of age. In another embodiment, the subject to be treated is about 9 years of age. In another embodiment, the subject to be treated is about 10 years of age. In another embodiment, the subject to be treated is about 11 years of age. In another embodiment, the subject to be treated is about 12 years of age. In another embodiment, the subject to be treated is about 13 years of age. In another embodiment, the subject to be treated is about 14 years of age. In another embodiment, the subject to be treated is about 15 years of age. In another embodiment, the subject to be treated is about 16 years of age. In another embodiment, the subject to be treated is about 17 years of age. In another embodiment, the subj ect to be treated is about 18 years of age. In another embodiment, the subj ect to be treated is about 19 years of age. In another embodiment, the subject to be treated is about 20 years of age. In another embodiment, the subject to be treated is about 21 years of age. In another embodiment, the subject to be treated is about 22 years of age. In another embodiment, the subject to be treated is about 23 years of age. In another embodiment, the subject to be treated is about 24 years of age. In another embodiment, the subject to be treated is about 25 years of age. In another embodiment, the subject to be treated is about 26 years of age. In another embodiment, the subject to be treated is about 27 years of age. In another embodiment, the subject to be treated is about 28 years of age. In another embodiment, the subject to be treated is about 29 years of age. In another embodiment, the subject to be treated is about 30+ years of age. In any of such embodiments, the subject can be biologically male. In any of such embodiments, theWSGR Ref. No.: 64320-710.601subject can be biologically female. A subject to be treated with the methods described herein can exhibit an improved quality of life following treatment. Alternatively, or in addition, a subj ect to be treated with the methods described herein can exhibit an improved quantity of life following treatment.Administration can be via any suitable method including, but not limited to, intravenous infusion.

[0126] The nMPCs, secretomes, and / or exosomes as provided herein are useful for treating a dystrophinopathy. In some embodiments, the nMPCs, secretomes, and / or exosomes as provided herein are useful for treating cardiomyopathy associated with a dystrophinopathy.

[0127] In one aspect, provided herein is a method of treating a dystrophinopathy in a subject in need thereof, comprising administering to the subject neonatal cardiac mesenchymal progenitor cells, whereby the dystrophinopathy is treated. In one embodiment, nMPCs to be administered in the described methods are human nMPCs. In one embodiment, nMPCs to be administered in the described methods are allogeneic. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p16INK4a; and whereby the dystrophinopathy is treated. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a. In another embodiment, the nMPCs are (a) positive for protein expression of Ki67 and Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and p16INK4a. In certain embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2. In some embodiments, the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2. Alternatively, or in addition, the nMPCs are further negative for protein expression of p16INK4aup to at least passage 8. In some embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-kit (CD 117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl 6INK4a. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2, (b) positive for cell surface protein expression ofc-kit (CD117), CD44, CD73, CD47, CD105, CD90, or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1,WSGR Ref. No.: 64320-710.601SSEA3, SSEA4, or pl6INK4a. Inyet other embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

[0128] In some embodiments, the nMPCs are genetically engineered. In other embodiments, the nMPCs are genetically engineered to overexpress one or more paracrine factors. In some embodiments, the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In some embodiments, the nMPCs are genetically engineered to overexpress 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, andpl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In some embodiments, the nMPCs are allogeneic or autologous. In certain embodiments, the nMPCs are non-naturally occurring. In other embodiments, the nMPCs are not xenogenic. In some embodiments, the nMPCs are obtained from a subject who is biologically a female. In certain other embodiments, the nMPCs are obtained from a subject who is biologically a male.

[0129] Alternatively, or in addition, in another aspect, provided herein is a method of treating a dystrophinopathy in a subject in need thereof, comprising administering to the subject an nMPC secretome, whereby the dystrophinopathy is treated. Alternatively, or in addition, in another aspect, the subject is administered an nMPC secretome (nMPC conditioned media) described herein. In another aspect, the subject is administered nMPC exosomes. In yet another aspect, the subject is administered an nMPC Total Secretome comprising both an nMPC secretome and nMPC exosomes. In one embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF -la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expressionWSGR Ref. No.: 64320-710.601of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p. In one embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. In another embodiment, the nMPC secretome and / or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p. In certain embodiments, the nMPC secretome and / or nMPC exosomes are positive for miRNA expression of one, two, three, four, five, or six of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p. Alternatively, or in addition, in another embodiment, an nMPC secretome and / or nMPC exosomes are positive for one, two, three, four, five, six, seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUM01, EIF3A, ECHI, HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RAB1A, RAB1B, PGRMC1, ERH, TIGAR, ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP100, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY I. AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH, DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS, TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1, NMT2, MAT2A, PRMT1, COX17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RAB11A, RABI IB, EIF5, COPZ1, COPS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2, TOMI, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2, TRIP10, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9, MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, OS9, ILF3, ISOC1, PPP1R7, MAPK1, PDCD1LG2, GOLGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orf166, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14, PLAUR, CXCL3, FASN, COPB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, COL16A1, PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TROVE2, MACF1, EIF5B, STX7,WSGR Ref. No.: 64320-710.601PFDNS, AP0A1, PDAP1, STX12, EIF3K, FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28. PPIC, NARS, PCBP2, CD2AP, PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1, MAN1A1, DDB1, PTBP1, FBN2, CNBP, OTUB1, NASP, HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS, ILF2, COPB1, PA2G4, COP A, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, and EPB41L3. Alternatively, or in addition, an nMPC secretome and / or nMPC exosomes are positive for one, two, three, four, five, six, seven, eight, nine, ten, or more of PPP1CA, PPP1CC, ST13, ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, NEDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, EN01, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPA0, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, 42254, and PAFAH1B2. In one instance, the nMPC secretome and / or nMPC exosomes do not comprise 42254. Alternatively, or in addition, an nMPC secretome and / or nMPC exosomes are positive for one, two, three, four, five, six, seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUM01, EIF3A, ECHI, HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RAB1A, RAB1B, PGRMC1, ERH, TIGAR, ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP100, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY1, AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH, DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS, TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1, NMT2, MAT2A, PRMT1, COX17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RABI 1 A, RABI IB, EIF5, COPZ1, COPS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2, TOMI, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2, TRIP10, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9,WSGR Ref. No.: 64320-710.601MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, 0S9, ILF3, ISOC1, PPP1R7, MAPK1, PDCD1LG2, G0LGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orfl66, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14, PLAUR, CXCL3, FASN, COPB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, COL16A1, PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TROVE2, MACF1, EIF5B, STX7, PFDNS, APOA1, PDAP1, STX12, EIF3K, FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28, PPIC, NARS, PCBP2, CD2AP, PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1, MAN1A1, DDB1, PTBP1, FBN2, CNBP, OTUB1, NASP, HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS, ILF2, COPB1, PA2G4, COP A, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, EPB41L3 PPP1CA, PPP1CC, STI3. ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, NEDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, ENO1, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPA0, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, 42254, and PAFAH1B2. In one instance, the nMPC secretome does not comprise 42254.

[0130] Alternatively, or in addition, in another aspect, the subject is administered nMPC exosomes described herein. Alternatively, or in addition, in another aspect, the subject is administered an nMPC total secretome which comprises an nMPC secretome described herein and an nMPC exosome described herein.

[0131] In any of such methods, a symptom of dystrophinopathy is improved by 2% or more, or by 2-fold or more, following treatment as compared to a placebo or compared to the subj ect prior to treatment. In some cases, a symptom is decreased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1 -fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subject prior to treatment. In some embodiments, a symptom is improvedWSGR Ref. No.: 64320-710.601about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5 -fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1 -fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subject prior to treatment.

[0132] In some embodiments, a symptom of dystrophinopathy improves by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0133] Symptoms of dystrophinopathy can comprise any one of reduced motor neuron function, muscle loss, muscle weakness or reduced muscle strength, reduced muscle regeneration, reduced flexibility, low range of motion, low stamina, fatigue, decreased blood flow, low cognition, low pulmonary function, inflammation, muscle fibrosis, muscle wasting or muscle necrosis, joint contracture, skeletal deformation, cardiomyopathy, impaired swallowing, impaired bowel and bladder function, muscle ischemia, cognitive impairment, behavioral dysfunction, socialization impairment, scoliosis, and impaired respiratory function. Other symptoms of dystrophinopathy to be treated include, but are not limited to, stiffness of joints, wasting or weakening of muscles (e.g, muscles in the shoulders, upper arms and calves), heart conditions (e.g, palpitations, presyncope, syncope, poor exercise tolerance, congestive heart failure, variable cardiac rhythm disturbances, bradycardia, atrial ventricular conduction defects, heart blockage, ventricular myocardial disease with failure and stroke, secondary to cardiac arrhythmia etc.), fainting, an awkward gait, a tendency for toe walking, fixed equinus deformities of the ankles, flexion contractures of the elbows, extension contracture of the neck, tightness of the lumbar paravertebral muscles, respiratory insufficiency, muscle wasting (e.g., of biceps, triceps, clavicular head of the pectoral muscles, abdomen, ankles, tibialis anterior muscle, etc. ), restrictive lung disease, intellectual disability, epilepsy, facial weakness, delayed motor milestones, progressive limb -girdle pattern of weakness, marked muscle wasting, hyperlordosis, loss of ambulation, ptosis, head drop, joint contractures, cardiomyopathy, weakness of the orbicularis oris muscle, limited facial expression, transverse smile, incomplete burying of eyelashes, forced eye closure, scapular winging, hearing loss, retinal vasculopathy (Coats disease), retinal detachment, blindness, progressive muscle wasting, atrophy of myocytes (affecting the eye and periocular muscles), extraocular muscle weakness, ptosis, disruptive eye movements dysphagia, impaired swallow efficiency, reduced pharyngeal constriction, reduced speed of hyoid movement, airway closure, oral regurgitation, nasal regurgitation, aspiration, post-swallow pharyngeal residue, esophageal retention, difficulty swallowing, weight loss, malnutrition, aspiration, facial weakness, hip weakness, shoulder weakness, change in voice quality, excessive fatigue, impairedWSGR Ref. No.: 64320-710.601cognitive function, extreme emaciation starvation, death, muscle weakness (distal and facial weakness of arms, hands, ankles, jaw, tongue or neck flexors), myotonia (often affecting the hands, tongue and jaw due to slow muscle relaxation), distal progressive muscle wasting, distal progressive muscle weakness, facial involvement, bulbar involvement, high palate, dysphonia, chronic pain (e.g., of the hands and feet), small fiber neuropathy, large fiber neuropathy, an increased risk for benign tumors, an increased risk for malignancies, and higher complications of adverse reactions to anesthesia and analgesic drugs relative to the general population, progressive cognitive decline, changes in brain white matter, fatigue, droopy eyelids, handshaking, breathing difficulties, swallowing difficulties, congenital hypotonia, delayed motor development, progressive muscle weakness, weak cry, poor feeding, weak muscle tone (hypotonia), damaged muscle fibers, atrophy of the skeletal muscles, weakness of the facial muscles, droopy eyelids (ptosis), an open mouth, joint deformities (contractures), impaired brain development, cobblestone lissencephaly, delayed development of speech and motor skills, moderate to severe intellectual disability, impaired social skills, seizures, impaired vision, eye abnormalities, progressive heart problems, swallowing difficulties, aspiration pneumonia, deterioration (atrophy) of skeletal muscles (limb -girdle muscle deterioration), late-onset distal myopathy (affecting ankles, feet or calves), respiratory insufficiency, cardiac failure, cardiac arrhythmia, skeletal muscle weakness due to impaired mitochondrial form and function, muscle rippling, myalgia, HyperCKemia, ankle contracture, calf hypertrophy, exercise intolerance, muscular cramps, fat infiltration, increased number of internal nuclei and rimmed vacuoles, cardiomyopathy, fatty replacement in semitendinosus, gastrocnemius and soleus, distal weakness, facial weakness, bulbar weakness, a pelvic lower girdle weakness, atrophy of the axial muscle and shoulder girdle, fatty replacement of fibers in pelvic and thigh muscles, cognitive impairment, decrease in a-dystroglycan glycosylation, myopia, epilepsy, cataracts, or a combination thereof.

[0134] In certain embodiments, a symptom of dystrophinopathy comprises reduced motor neuron function. In some embodiments, treatment with any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein improves motor neuron function by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment improves motor neuron function by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In certain embodiments, administration of a composition described herein inhibits or reduces motor neuron loss in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.WSGR Ref. No.: 64320-710.601

[0135] In some embodiments, a symptom of dystrophinopathy comprises muscle loss, muscle wasting, or muscle necrosis. In some embodiments, the treatment reduces muscle loss, muscle wasting, or muscle necrosis by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces muscle loss, muscle wasting, or muscle necrosis by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0136] In some embodiments, a symptom of dystrophinopathy comprises muscle weakness. In some embodiments, treatment with any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein reduces muscle weakness by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces muscle weakness by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment increases muscle strength or regeneration by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment increases muscle strength or regeneration by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment increases muscle flexibility by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment increases muscle flexibility by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment increases muscle range of motion by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the diseaseWSGR Ref. No.: 64320-710.601or condition prior to treatment with any composition described herein. In other embodiments, the treatment increases muscle range of motion by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment as described herein reduces muscle fibrosis by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces muscle fibrosis by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment as described herein reduces muscle necrosis by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces muscle necrosis by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0137] In some embodiments, treatment with any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein reduces joint contracture by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces joint contracture by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment reduces skeletal deformation by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces skeletal deformation by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.WSGR Ref. No.: 64320-710.601

[0138] In some embodiments, treatment with any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein increases stamina by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment increases stamina by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment reduces fatigue by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces fatigue by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment increases blood flow by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment increases blood flow by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0139] In some embodiments, treatment with any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein improves cognition by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment improves cognition by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment reduces behavioral dysfunction by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces behavioral dysfunction by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,WSGR Ref. No.: 64320-710.60160%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment as described herein reduces social impairment by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces social impairment by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0140] In some embodiments, treatment with any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein improves pulmonary function by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment improves pulmonary function by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment improves respiratory function by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment improves respiratory function by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0141] In some embodiments, treatment with any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein reduces inflammation by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment reduces inflammation by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In certain embodiments, the symptom of dystrophinopathy comprises high levels of pro-inflammatory cytokines (e.g, Interleukin (IL)- 1, IL-6, IL-8, IL-12, IL-17a, IL-18, MCP-1, tumor necrosis factor (TNF)-a, interferon gamma (IFN-y)). In someWSGR Ref. No.: 64320-710.601embodiments, the treatment reduces levels of pro-inflammatory cytokines by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein (e.g, secretomes, exosomes, peptides, proteins, nucleic acids, etc. ), such that the level of pro-inflammatory cytokines is considered clinically normal. In an embodiment, the treatment reduces levels of IL- 1 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In one embodiment, the treatment reduces levels of IL-6 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In another embodiment, the treatment reduces levels of IL-8 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In yet another embodiment, the treatment reduces levels of IL-12 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In certain other embodiments, the treatment reduces levels of IL-17a by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In another embodiment, the treatment reduces levels of IL-18 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In one embodiment, the treatment reduces levels ofMCP-1 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In another embodiment, the treatment reduces levels of TNF-aby at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment reduces levels of IFN-y by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,WSGR Ref. No.: 64320-710.60155%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In another embodiment, the treatment reduces levels of TNF-a, IL-8, MCP-1, IL- 17a, and IFN-y by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In another embodiment, the treatment reduces levels of TNF-a, IL-8, and MCP-1 by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of the nMPCs, an nMPC secretome, or nMPC exosomes. In another embodiment, the treatment reduces levels of IL- 17a and IFN-y by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to a placebo or compared to the subject prior to administration of the nMPCs, an nMPC secretome, or nMPC exosomes. In some embodiments, the treatment reduces oxidative stress in a subject by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In one embodiment, a composition described herein, when administered to a subject, regulates fibrosis, inflammation, or metabolism. In one embodiment, a composition described herein, when administered to a subject, promotes angiogenesis, endothelial repair, or anti-inflammatory factors, including, but not limited to, IL- 10 and suppression of pro-inflammatory cytokines (e.g., TNF-a, IL-6, IL- 1, IL18, CXCL9, matrix metalloproteinase 12 (MMP12)).

[0142] In some embodiments, treatment with any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein improves swallowing ability by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment improves swallowing ability by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, treatment with any composition comprising nMPCs, an nMPC secretome, or nMPC exosomes as described herein improves bowel and bladder function by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment improves bowel and bladder function by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,WSGR Ref. No.: 64320-710.60145%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0143] In certain embodiments, the symptom of dystrophinopathy comprises tow cardiac performance and / or tow left ventricular ejection fraction (LVEF). In some embodiments, the treatment improves cardiac performance by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment improves cardiac performance by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment improves left ventricular ejection fraction (LVEF) by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment improves left ventricular ejection fraction (LVEF) by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, an improvement in LVEF is a change in percentage of the measured LVEF to fall within standard range considered clinically normal. In some embodiments, the standard range considered clinically normal is an LVEF between about 50% and about 70%, about 50% and about 60%, about 50% and about 55%, about 55% and about 60%, about 60% and about 65%, about 60% and about 70%, or about 65% and about 70%. In some embodiments, the standard range considered mild dysfunction is an LVEF between about 40% and about 49%. In some embodiments, the standard range considered moderate dysfunction is an LVEF between about 30% and about 39%. In some embodiments, the standard range considered severe dysfunction is an LVEF less than about 30%. In some embodiments, an improvement in LVEF is a change in percentage of the measured LVEF to be above about 50%. In some embodiments, an improvement in LVEF is an increase in percentage of the measured LVEF prior to administration of nMPCs, an nMPC secretome, or nMPC exosomes as described herein. In some embodiments, an improvement in LVEF is an increase in percentage of the measured LVEF by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% above the initial LVEF percentage prior to administration of nMPCs, an nMPC secretome, or nMPC exosomes as described herein.

[0144] In certain embodiments, the likelihood or severity of, inhibit, or treat one or more symptoms of cardiomyopathy in a dystrophinopathy are reduced. In some embodiments, the dystrophinopathy isWSGR Ref. No.: 64320-710.601DMD. In some embodiments, the dystrophinopathy is BMD. In some embodiments, the cardiomyopathy is dilated cardiomyopathy. In some cases, a symptom is decreased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subject prior to treatment. In some embodiments, a symptom is improved about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5 -fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0145] In some embodiments, a symptom of cardiomyopathy in dystrophinopathy improves by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the dystrophinopathy is DMD. In some embodiments, the dystrophinopathy is BMD. In some embodiments, the cardiomyopathy is dilated cardiomyopathy. In certain embodiments, the symptom of a disease or condition comprises low cardiac performance and / or low left ventricular ejection fraction (LVEF). In some embodiments, the treatment improves cardiac performance by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment improves cardiac performance by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment improves left ventricular ejection fraction (LVEF) by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and asWSGR Ref. No.: 64320-710.601compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment improves left ventricular ejection fraction (LVEF) by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, an improvement in LVEF is a change in percentage of the measured LVEF to fall within standard range considered clinically normal. In some embodiments, the standard range considered clinically normal is an LVEF between about 50% and about 70%, about 50% and about 60%, about 50% and about 55%, about 55% and about 60%, about 60% and about 65%, about 60% and about 70%, or about 65% and about 70%. In some embodiments, the standard range considered mild dysfunction is an LVEF between about 40% and about 49%. In some embodiments, the standard range considered moderate dysfunction is an LVEF between about 30% and about 39%. In some embodiments, the standard range considered severe dysfunction is an LVEF less than about 30%. In some embodiments, an improvement in LVEF is a change in percentage of the measured LVEF to be above about 50%. In some embodiments, an improvement in LVEF is an increase in percentage of the measured LVEF as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, an improvement in LVEF is an increase in percentage of the measured LVEF by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% above the initial LVEF percentage as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0146] In certain embodiments, the likelihood or severity of, inhibit, or treat one or more symptoms of cardiomyopathy in BMD are reduced. In some cases, a symptom is decreased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to a subject treated with a placebo or compared to the subject prior to treatment. In some embodiments, a symptom is improved about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1 -fold, at leastWSGR Ref. No.: 64320-710.601about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0147] In some embodiments, a symptom of cardiomyopathy in BMD improves by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In certain embodiments, the symptom of a disease or condition comprises low cardiac performance and / or low left ventricular ejection fraction (LVEF). In some embodiments, the treatment improves cardiac performance by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In other embodiments, the treatment improves cardiac performance by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment improves left ventricular ejection fraction (LVEF) by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, the treatment improves left ventricular ejection fraction (LVEF) by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, an improvement in LVEF is a change in percentage of the measured LVEF to fall within standard range considered clinically normal. In some embodiments, the standard range considered clinically normal is an LVEF between about 50% and about 70%, about 50% and about 60%, about 50% and about 55%, about 55% and about 60%, about 60% and about 65%, about 60% and about 70%, or about 65% and about 70%. In some embodiments, the standard range considered mild dysfunction is an LVEF between about 40% and about 49%. In some embodiments, the standard range considered moderate dysfunction is an LVEF between about 30% and about 39%. In some embodiments, the standard range considered severe dysfunction is an LVEF less than about 30%. In some embodiments, an improvement in LVEF is a change in percentage of the measured LVEF to be above about 50%. In some embodiments, an improvement in LVEF is an increase in percentage of the measured LVEF as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein. In some embodiments, an improvement in LVEF is an increase in percentage of the measured LVEF by aboutWSGR Ref. No.: 64320-710.6012%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% above the initial LVEF percentage as compared to after treatment with a placebo and as compared to a symptom of the disease or condition prior to treatment with any composition described herein.

[0148] In any method described herein, a metric for assessing cardiomyopathy associated with a dystrophinopathy is improved in a subject administered a composition comprising nMPCs, nMPC secretome, and / or nMPC exosomes, as compared to a subject administered a placebo. In certain embodiments, the cardiomyopathy is dilated cardiomyopathy (DCM). In some embodiments, the subject is diagnosed with a dystrophinopathy as described herein. In some embodiments, the dystrophinopathy is DMD. In some embodiments, the dystrophinopathy is BMD. A metric for assessing cardiomyopathy can comprise a Stroke Volume Index (SVI), a 6-minute walk test (6MWT), a Kansas City Cardiomyopathy Questionnaire (KCCQ), Left Ventricular (LV) Filling Pressure or a Diastolic Dysfunction (E / e’ mean), N-terminal pro-B-type natriuretic peptide (NT-proBNP), High-Sensitivity C-Reactive Protein (hs-CRP), Estimated Glomerular Filtration Rate (eGFR), and / or End-Diastolic Volume Index (EDVI).Stroke Volume Index (SVI)

[0149] Stroke Volume Index (SVI) is a measurement of the volume of blood ejected by a ventricle per heartbeat, normalized to a subject’s body surface area, and expressed in units of mL / m2. It is calculated by dividing the stroke volume (SV) by the body surface area (BSA): SVI = SV / BSA. SVI is used as a tool for assessing cardiac function and to diagnose and monitor conditions like aortic stenosis, where a low SVI (e. g., < 35 mL / m2) can indicate a problem with the heart's output. In one aspect, provided herein is a method of improving a stroke volume index (SVI) in a subject diagnosed with a symptom of dystrophinopathy or cardiomyopathy associated with dystrophinopathy, comprising intravenously administering to the subject a composition comprising about 50×106, about 100×106, about 150×106, or about 200×106nMPCs, wherein the subject exhibits an improvement in SVI following treatment. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the SVI following treatment compared to baseline or compared to a placebo. In some embodiments, the SVI increases by at least about 2 mL / m2, at least about 2.5 mL / m2, at least about 3 mL / m2, about 3.5 mL / m2, at least about 4 mL / m2, at least about 4.5 mL / m2, at least about 5 mL / m2, at least about 5.5 mL / m2, at least about 6 mL / m2, at least about 6.5 mL / m2, at least about 7 mL / m2, at least about 7.5 mL / m2, at least about 8 mL / m2, at least about 8.5 mL / m2, at least about 9 mL / m2, at least about 9.5 mL / m2, or at least about 10 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 2 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 4 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 5 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 6 mL / m2following treatment compared to baseline. In some embodiments, the SVI increases by at least about 9 mL / m2following treatment compared to baseline.WSGR Ref. No.: 64320-710.6016-minute walk test (6MWT)

[0150] The 6-minute walk test (6MWT) is a widely used, standardized test that measures the distance a patient can walk in 6 minutes to assess their functional exercise capacity. It is a self-paced test performed in a standard environment where the patient walks back and forth and can rest as needed, with the total distance covered recorded as the score. The 6MWT helps evaluate the degree of functional impairment, guides treatment decisions, and can serve as a predictor of morbidity and mortality. Before and after the walk, the subject’s pulse, blood pressure, and oxygen saturation (SpO2) are measured with subjective ratings of breathlessness. The total distance walked is the main score and is interpreted in the context of a subject’s age, sex, height, weight, and specific health condition. In one aspect, provided herein is a method of treating a subject diagnosed with a symptom of dystrophinopathy or cardiomyopathy associated with dystrophinopathy, comprising intravenously administering to the subject a composition comprising about 50*106, about 100*106, about 150*106, or about 200*106nMPCs, wherein the subject exhibits an improvement in a 6-minute walk test (6MWT) following treatment. Generally, a greater amount of distance walked corresponds to greater functional exercise capacity, and a lower amount of distance walked corresponds to lower functional exercise capacity. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the 6MWT following treatment compared to baseline or compared to a placebo. In some embodiments, the 6MWT increases by at least about 20 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 50 meters following treatment compared to baseline. In some embodiments, an increase in the distance walked during the 6MWT corresponds to an improvement following treatment compared to baseline or compared to a placebo. In some embodiments, the subject exhibits at least a 2% improvement in the 6MWT following treatment compared to baseline or compared to a placebo. In some embodiments, the 6MWT increases by at least about 2 meters, at least about 4 meters, at least about 6 meters, at least about 8 meters, at least about 9 meters, at least about 10 meters, at least about 12 meters, at least about 14 meters, at least about 16 meters, at least about 18 meters, at least about 20 meters, at least about 22 meters, at least about 24 meters, at least about 25 meters, at least about 26 meters, at least about 28 meters, at least about 30 meters, at least about 40 meters, or at least about 50 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 2 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 9 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 16 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 22 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 25 meters following treatment compared to baseline. In some embodiments, the 6MWT increases by at least about 50 meters following treatment compared to baseline.WSGR Ref. No.: 64320-710.601Kansas City Cardiomyopathy Questionnaire (KCCQ)

[0151] The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23 -item self-administered questionnaire used to measure a subject’s perception of their own health status, which includes heart failure symptoms, impact on physical and social function, and how their heart failure impacts their quality of life (QOL) within a 2- week recall period. The KCCQ tool quantifies the following six distinct domains and two summary scores. The six KCCQ domains include (1) KCCQ Symptom Domain, (2) KCCQ Physical Function Domain, (3) KCCQ Quality of Life Domain, (4) KCCQ Social Limitation Domain, (5) KCCQ Self-efficiency Domain, and (6) KCCQ Symptom Stability Domain. The two KCCQ summary scores include (1) Clinical Summary Score and (2) Overall Summary Score. An overall symptom score is generally used in analyses; subscale scores for both frequency and severity are also available. The KCCQ Symptom Domain quantifies the frequency and burden of clinical symptoms in heart failure, such as, for example, fatigue, shortness of breath, paroxysmal nocturnal dyspnea and a subject’s edema or swelling. The KCCQ Physical Function Domain measures the limitations subjects experience due to heart failure symptoms in performing routine activities. Activities are common, gender-neutral, and generalizable across cultures, while also capturing a range of exertional requirements. The KCCQ Quality of Life Domain is designed to reflect a subject’s assessment of their quality of life, given the current status of their heart failure. The KCCQ Social Limitation Domain quantifies the extent to which heart failure symptoms impair a subject’s ability to interact in a number of gender-neutral social activities. The KCCQ Self-efficacy Domain quantifies a subject’s perceptions of how to prevent heart failure exacerbations and manage complications when they arise. This scale is not included in the summary scores. The KCCQ Symptom Stability Domain measures recent changes in a subject’s symptoms, their shortness of breath, fatigue or swelling, and compares a subject’s frequency of heart failure symptoms at the time of completing the KCCQ with their frequency 2 weeks ago. As a measure of change, it is most interpretable as a baseline assessment of the stability of a subject’s symptoms at the start of a study and shortly thereafter, as a measure of the acute response to treatment. This domain is not included in the summary scores. In one aspect, provided herein is a method of treating a subject diagnosed with a symptom of dystrophinopathy or cardiomyopathy associated with dystrophinopathy, comprising intravenously administering to the subject a composition comprising about 50*106, about 100*106, about 150*106, or about 200*106nMPCs, wherein the subject exhibits an improvement as determined by a Kansas City Cardiomyopathy Questionnaire (KCCQ) following treatment. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the KCCQ following treatment compared to baseline or compared to a placebo. In some embodiments, the KCCQ increases by about 5, about 10, about 15, about 20, about 25, or about 30 points following treatment compared to baseline. In some embodiments, the subject improves from a “good to fair health status” to a “good to excellent health status” as determined by the KCCQ following treatment compared to baseline. A KCCQ score of below 75 points indicates good to fair health status and a score of 75 or above indicates good to excellent health status. In some embodiments, the subjectWSGR Ref. No.: 64320-710.601exhibits at least a 2% improvement in the KCCQ following treatment compared to baseline or compared to a placebo. In some embodiments, the KCCQ increases by at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, or at least about 30 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 9 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 17 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 18 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 20 points following treatment compared to baseline. In some embodiments, the KCCQ increases by at least about 21 points following treatment compared to baseline, n some embodiments, the subject improves from a “good to fair health status” to a “good to excellent health status” as determined by the KCCQ following treatment compared to baselineLeft Ventricular (LV) Filling Pressure or a Diastolic Dysfunction (E / e’ mean)

[0152] Left ventricular filling pressure or a diastolic dysfunction was assessed by measurements of each patient’s tissue Doppler-derived E / e’ ratio. A normal E / e’ ratio is generally considered to be less than 8. A ratio greater than about 15 suggests elevated filling pressures, a ratio greater than about 13 is correlated with a disease state, and a ratio between about 8 and about 13 is correlated with an intermediate range where other echocardiographic findings are necessary to determine diastolic function. The E / e’ ratio is calculated by dividing the peak E-wave velocity by the average peak early diastolic mitral annular velocity (e1). This ratio is generally measured on both the septal and lateral mitral annulus and averaged. In one aspect, provided herein is a method of improving a left ventricular filling pressure or a diastolic dysfunction in a subject diagnosed with a symptom of dystrophinopathy or cardiomyopathy associated with dystrophinopathy, comprising intravenously administering to the subject a composition comprising about 50*106, about 100*106, about 150*106, or about 200*106nMPCs, wherein the subject exhibits an improvement in left ventricular filling pressure or diastolic dysfunction following treatment. In some embodiments, the subject exhibits at least about a 2% improvement in the left ventricular filling pressure following treatment compared to baseline or compared to a placebo. In some embodiments, the subject exhibits at least about a 2% improvement in the diastolic dysfunction following treatment compared to baseline or compared to a placebo. In some embodiments, an E / e’ mean of the subject improves from a diseased level (>13) to a non- diseased level (<13) following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 0.5, at least about 0.75, at least about 1, at least about 1.25, at least about 1.5, at least about 1.75, at least about 2, at least about 2.25, at least about 2.5, at least about 2.75, at least about 3, at least about 3.25, at least about 3.5, at least about 3.75, at least about 4, at least about 4.5, or at least about 5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 0.5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreasesWSGR Ref. No.: 64320-710.601by a score of at least about 1 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 1.5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 2 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 2.25 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by at least about 2% following treatment compared to baseline. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the left ventricular filling pressure following treatment compared to baseline or compared to a placebo. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% improvement in the diastolic dysfunction following treatment compared to baseline or compared to a placebo. In some embodiments, an E / e’ mean of the subject improves from a diseased level (>13) to a non-diseased level (<13) following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by a score of at least about 0.5 following treatment compared to baseline. In some embodiments, an E / e’ mean of the subject decreases by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% following treatment compared to baseline.N-terminal pro-B-type natriuretic peptide (NT -proBNP)

[0153] NT-proBNP Reduction and HF Biomarkers: the nMPC secretome leads to a significant decrease inNT-proBNP level, a key biomarker of heart failure severity. This reduction is mediated by improved ventricular relaxation, reduced myocardial stress, and anti-inflammatory effects. N-terminal pro-B-type natriuretic peptide levels are measured in the blood of patients. In one aspect, provided herein is a method of decreasing a level of an N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a subject diagnosed with a symptom of dystrophinopathy or cardiomyopathy associated with dystrophinopathy, comprising intravenously administering to the subject a composition comprising about 50×106, about 100×106, about 150×106, or about 200×106nMPCs, wherein the subject exhibits a decreased level of the NT-proBNP following treatment. In some embodiments, the subject to be treated has an elevated level of NT-proBNP prior to treatment. In some embodiments, the subject to be treated has a level of NT-proBNP of >240 pg / mL prior to treatment. In certain embodiments, the subject to be treated has a level of NT-proBNP of >100 pg / mL prior to treatment. In certain other embodiments, the subject to be treated has a level ofNT-proBNP of <100 pg / mL prior to treatment. In some embodiments, the subject to be treated has a level ofNT-proBNP of <240 pg / mL following treatment. In some other embodiments, the subject to be treated has a level ofNT-proBNP of <100 pg / mL following treatment. In some embodiments, NT-proBNP levels vary depending on age and other factors. In certain embodiments, a level ofNT-proBNP of less than about 125 pg / mL is associated with a lower likelihood to have heart failure. In one embodiment, a level ofNT-proBNP of between about 125 and about 900 pg / mL is associated with possible heart failure. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%,WSGR Ref. No.: 64320-710.6017%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% decrease in the level of NT-proBNP of <240 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 2 pg / mL, 4 pg / mL, 6 pg / mL, 8 pg / mL, 10 pg / mL, about 20 pg / mL, about 30 pg / mL, about 40 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL, or more, following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 2 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 10 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 12 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 20 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 30 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 40 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in the level of NT-proBNP of at least about 50 pg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a blood level of NT-proBNP of over about 125 pg / mL, about 150 pg / mL, about 175 pg / mL, about 200 mg / mL, about 225 pg / mL, about 250 pg / mL, or about 275 pg / mL prior to treatment. In some embodiments, the subject exhibits a blood level of NT-proBNP of at least about 10 pg / mL, about 20 pg / mL, about 30 pg / mL, about 40 pg / mL, about 50 pg / mL, about 60 pg / mL, about 70 pg / mL, about 80 pg / mL, about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL, about 140 pg / mL, about 150 pg / mL, about 160 pg / mL, about 170 pg / mL, about 180 pg / mL, about 190 pg / mL, about 200 pg / mL, about 210 pg / mL, about 220 pg / mL, about 230 pg / mL, about 240 pg / mL, about 250 pg / mL, about 260 pg / mL, about 270 pg / mL, about 280 pg / mL, about 290 pg / mL, about 300 pg / mL prior to treatment. In some embodiments, the subject exhibits a blood level of NT-proBNP of over about 250 pg / mL, about 300 pg / mL, about 400 pg / mL, about 500 pg / mL, about 600 pg / mL, about 700 pg / mL, about 800 pg / mL, about 900 pg / mL, or more prior to treatment.High-Sensitivity C-Reactive Protein (hs-CRP)

[0154] hs-CRP is a blood test that measures levels of C-reactive protein (CRP), which is an inflammatory marker produced by the liver in response to inflammation. The normal range for hs-CRP is typically less than 1.0 mg / L, and low hs-CRP levels generally correspond to a lack of inflammation. An hs-CRP range of between about 1.0 and 3.0 mg / L indicates moderate risk for heart attack, stroke, and other cardiovascular issues, even in otherwise healthy individuals. An hs-CRP value above about 3.0 mg / L indicates a high risk for cardiovascular disease. Elevated hs-CRP levels indicate inflammation inWSGR Ref. No.: 64320-710.601the body, and can be associated with an increased risk of heart disease, stroke, and other cardiovascular events. A value above about 10 mg / L corresponds to a marked elevation corresponding to significant inflammation caused by factors, including, but not limited to, infections, autoimmune diseases, heart disease, and cancer. From baseline to Day 56, subjects administered the nMPCs were observed to experience a decrease in hs-CRP in a range between about 0.2 mg / L and 2.1 mg / L. In some embodiments, the subject to be treated has an elevated level of CRP prior to treatment as assessed by a high- sensitivity C-Reactive Protein (hs-CRP) blood test. In some embodiments, the subject to be treated has a CRP level greater than about 1.0 mg / L, about 1.5 mg / L, about 3.0 mg / L, about 5.0 mg / L, or about 10.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 1.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 1.5 mg / L prior to treatment. In some embodiments, the subj ect to be treated has a CRP level greater than about 2.0 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 2.5 mg / L prior to treatment. In some embodiments, the subject to be treated has a CRP level greater than about 3.0 mg / L prior to treatment. In some embodiments, the subject exhibits at least about a 2% decrease in CRP level of at least about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.75 mg / mL, about 1.0 mg / mL, about 1.5 mg / mL about 2.0 mg / mL, about 2.5 mg / mL, or about 3.0 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.1 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.2 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 0.5 mg / mL following treatment compared to baseline. In some embodiments, the subj ect exhibits a decrease in CRP level of at least about 1.0 mg / mL following treatment compared to baseline. In some embodiments, the subject exhibits a decrease in CRP level of at least about 2.0 mg / mL following treatment compared to baseline.Estimated Glomerular Filtration Rate (eGFR)

[0155] Estimated glomerular filtration rate is a calculation from a blood test that estimates a subject’s kidney’s efficiency in fdtering waste and excess fluid from blood. A normal eGFR is generally about 90 milliliters per minute per 1.73 square meters (mL / min / 1.73 m2) or higher, but the number decreases with age. An eGFR below 60 mL / min / 1.73 m2for three months or more, especially with signs of kidney damage like protein in urine, can be indicative of chronic kidney disease (CKD). A low eGFR are characteristic of poor kidney function, and eGFR may be used to diagnose, stage, monitor kidney disease, and adjust medications. In some embodiments, the subject to be treated has a reduced eGFR prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 89 mL / min / 1.73 m2, about 85 mL / min / 1.73 m2, about 80 mL / min / 1.73 m2, about 75 mL / min / 1.73 m2, about 70 mL / min / 1.73 m2, about 65 mL / min / 1.73 m2, about 60 mL / min / 1.73 m2, about 55 mL / min / 1.73 m2, about 50 mL / min / 1.73 m2, or about 45 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 80 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject to be treated has an eGFR lower than about 70 mL / min / 1.73 m2prior to treatment. In someWSGR Ref. No.: 64320-710.601embodiments, the subject to be treated has an eGFR lower than about 60 mL / min / 1.73 m2prior to treatment. In some embodiments, the subject exhibits at least about a 2% increase in an eGFR of at least about 0.5 mL / min / 1.73 m2, about 1 mL / min / 1.73 m2, about 1.5 mL / min / 1.73 m2, about 2 mL / min / 1.73 m2, about 2.5 mL / min / 1.73 m2, about 3 mL / min / 1.73 m2, about 3.5 mL / min / 1.73 m2, about 4 mL / min / 1.73 m2, about 4.5 mL / min / 1.73 m2, about 5 mL / min / 1.73 m2, about 5.5 mL / min / 1.73 m2, about 6 mL / min / 1.73 m2, about 6.5 mL / min / 1.73 m2, about 7 mL / min / 1.73 m2, about 7.5 mL / min / 1.73 m2, about 8 mL / min / 1.73 m2, about 8.5 mL / min / 1.73 m2, about 9 mL / min / 1.73 m2, about 9.5 mL / min / 1.73 m2, about 10 mL / min / 1.73 m2, about 11 mL / min / 1.73 m2, about 12 mL / min / 1.73 m2, about 13 mL / min / 1.73 m2, about 14 mL / min / 1.73 m2, about 15 mL / min / 1.73 m2, about 17.5 mL / min / 1.73 m2, or about 20 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 0.5 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 1 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 4 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 6 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 8 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 9 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 10 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 11 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subject exhibits an increase in an eGFR of at least about 12 mL / min / 1.73 m2following treatment compared to baseline. In some embodiments, the subj ect exhibits an increase in an eGFR of at least about 13 mL / min / 1.73 m2following treatment compared to baseline.End-Diastolic Volume Index (EDVI)

[0156] The end-diastolic volume index (EDVI) is the amount of blood in a heart ventricle at the end of diastole (or end-diastolic volume, EDV) divided by a patient’s body surface area (BSA). EDVI is a parameter used to assess the heart’s ability to fill with blood and its overall function. EDVI helps determine the preload, which is the blood volume that stretches the heart muscle before it contracts. EDVI is determined using techniques like, for example, but not limited to, cardiac MRI, or other imaging modalities. End-diastolic volume tends to decrease with age. Generally, men have larger total blood volume than women. Body surface area also influences blood volume. In one aspect, provided herein is a method of increasing end-diastolic volume in a subject diagnosed with a symptom of a dystrophinopathy or cardiomyopathy associated with dystrophinopathy, comprising intravenously administering to the subject a composition comprising about 50*106, about 100xl06, about 150x106, or about 200x106nMPCs, wherein the subject exhibits an increase in end-diastolic volume following treatment. In some embodiments, the subject to be treated has a low end-diastolic volume prior to treatment. In some instances, a low end-diastolic volume corresponds to reduced filling of the ventricles and lower cardiacWSGR Ref. No.: 64320-710.601output. In some embodiments, the subject to be treated is male and has a left ventricular end-diastolic volume of less than about 60 mL / m2, about 55 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment. In some embodiments, the subject to be treated is female and has a left ventricular end-diastolic volume of less than about 56 mL / m2, about 55 mL / m2, about 54 mL / m2, about 53 mL / m2, about 52 mL / m2, about 51 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment. In some embodiments, the subject to be treated is male and has a right ventricular end-diastolic volume of less than about 64 mL / m2, 60 mL / m2, about 55 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment. In some embodiments, the subject to be treated is female and has a right ventricular end-diastolic volume of less than about 57 mL / m2, 56 mL / m2, about 55 mL / m2, about 54 mL / m2, about 53 mL / m2, about 52 mL / m2, about 51 mL / m2, about 50 mL / m2, about 45 mL / m2, about 40 mL / m2, about 35 mL / m2, or about 30 mL / m2prior to treatment. In some embodiment^ a normal left ventricular end-diastolic volume for a male subject is from about 60 to about 109 mL / m2. In some embodiments, a normal left ventricular end-diastolic volume for a male subject is from about 56 mL / m2to about 96 mL / m2. In some embodiments, a normal left ventricular end-diastolic volume for a male subject is from about 64 mL / m2to about 115 mL / m2. In some embodiments, a normal left ventricular end-diastolic volume for a male subject is from about 57 mL / m2to about 99 mL / m2. In some embodiments, the subject to be treated has an increase in EDVI of at least about 0.5 mL / m2, about 0.75 mL / m2, about 1.0 mL / m2, about 1.25 mL / m2, about 1.5 mL / m2, about 1.75 mL / m2, about 2.0 mL / m2, about 2.25 mL / m2, about 2.5 mL / m2, about 2.75 mL / m2, about 3.0 mL / m2, about 3.25 mL / m2, about 3.5 mL / m2, about 3.75 mL / m2, about 4.0 mL / m2, about 4.25 mL / m2, about 4.5 mL / m2, about 4.75 mL / m2, about 5.0 mL / m2, about 5.25 mL / m2, about 5.5 mL / m2, about 5.75 mL / m2, about 6.0 mL / m2, about 6.25 mL / m2, about 6.5 mL / m2, about 6.75 mL / m2, about 7.0 mL / m2, about 7.25 mL / m2, about 7.5 mL / m2, about 7.75 mL / m2, about 8.0 mL / m2, about 8.25 mL / m2, about 8.5 mL / m2, about 8.75 mL / m2, about 9.0 mL / m2, about 9.25 mL / m2, about 9.5 mL / m2, about 9.75 mL / m2, or about 10.0 mL / m2following treatment compared to baseline. In some embodiments, the subject to be treated has in increase in EDVI of at least about 2 mL / m2following treatment compared to baseline. In some embodiments, the subject to be treated has in increase in EDVI of at least about 5 mL / m2following treatment compared to baseline. In some embodiments, the subject to be treated has in increase in EDVI of at least about 7 mL / m2following treatment compared to baseline. In some embodiments, the subject to be treated has in increase in EDVI of at least about 9 mL / m2following treatment compared to baseline. In some embodiments, the subject to be treated has in increase in EDVI of at least about 10 mL / m2following treatment compared to baseline. In some embodiments, the subject exhibits at least about a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% increase in EDVI following treatment compared to baseline.Dosing and Dosing Schedules

[0157] In certain aspects, the compositions nMPCs, an nMPC secretome, or nMPC exosomes are formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form asWSGR Ref. No.: 64320-710.601used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with a pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure is dictated by, and directly dependent on, the unique characteristics of the compositions and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an agent for the treatment of subjects. In various embodiments, the administration can be in repeated doses, such as two, three, four, four or more sequentially applied doses. In various embodiments, the repeated or sequentially applied doses are provided for treatment of a disease and / or condition. In some embodiments, the disease and / or condition can be chronic or acute. In various embodiments, the repeated or sequentially applied doses are provided for treatment of a symptom of an acute disease and / or condition. In various embodiments, the repeated or sequentially applied doses are provided for treatment of a symptom of dystrophinopathy. In certain embodiments, the repeated or sequentially applied doses are provided for treatment of a symptom of dystrophinopathy or cardiomyopathy associated with dystrophinopathy. In some instances, a dystrophinopathy can be a hereditary muscular dystrophy, an acquired muscular dystrophy, or an intermediate phenotype muscular dystrophy. In some instances, a dystrophinopathy comprises DMD, BMD, a DMD-associated dilated cardiomyopathy (DCM), a limb-girdle muscular dystrophy (LGMD), a congenital muscular dystrophy, a congenital myopathy, a distal hereditary myopathy, a facioscapulohumeral muscular dystrophy (FSHD), an oculopharyngeal muscular dystrophy (OPMD), Emery-Dreifuss muscular dystrophy (EDMD), a congenital muscular dystrophy, a Congenital myopathy, a Myofibrillar myopathy, an Inclusion body myositis (IBM), a myotonic dystrophy, a metabolic myopathy, a mitochondrial myopathy, or an inflammatory myopathy. In one instance, cardiomyopathy associated with dystrophinopathy is X-linked cardiomyopathy.

[0158] As used herein, “first dose” and “starting dose” represent the first dose out of one or more doses administered to a subject. In some embodiments, the method as described herein comprises administering to the human subject a pharmaceutical composition comprising the nMPCs, nMPC secretome, and / or nMPC exosomes at a first dose at a concentration of from about 0.5*106nMPCs per kilogram of subject body weight (cells / kg or nMPCs / kg) to about 50x106nMPCs / kg, and one or more further maintenance doses, wherein the one or more further maintenance doses contain a dose concentration that is different from the first dose concentration. In some embodiments, the method as described herein comprises administering to the human subject a pharmaceutical composition comprising the nMPCs, nMPC secretome, and / or nMPC exosomes at afirst dose comprising an amount of from about 40x106nMPCs to about 400x106nMPCs per dose, and one or more further maintenance doses, wherein the one or more further maintenance doses contain a dose amount that is different from the first dose amount. In some embodiments, the method as described herein comprises administering to the human subject a pharmaceutical composition comprising the nMPCs, nMPC secretome, and / or nMPC exosomes at a first dose comprising an amount of from about 5.0* 107nMPCs to about 2.5 * 108nMPCs per dose, and one or more further maintenance doses, wherein the one or more further maintenance doses contain a doseWSGR Ref. No.: 64320-710.601amount that is different from the first dose amount. In one embodiment, the first dose comprises about 50* 106cells. In one embodiment, the first dose comprises about 100* 106cells. In one embodiment, the first dose comprises about 150* 106cells. In one embodiment, the first dose comprises about 200* 106cells. In an embodiment, the first dose is administered to the subj ect at a concentration of about 0.5 * 106nMPCs per kilogram of subject body weight (cells / kg). In an embodiment, the first dose is administered to the subject at a concentration of about 0.625* 106cells / kg. In an embodiment, the first dose is administered to the subject at a concentration of about 0.7* 106cells / kg. In an embodiment, the first loading dose comprises a concentration of about 1.0* 106cells / kg. In an embodiment, the first dose is administered to the subj ect at a concentration of about 1.25 * 106cells / kg. In an embodiment, the first dose is administered to the subject at a concentration of about 1.43*106cells / kg. In an embodiment, the first dose is administered to the subject at a concentration of about 2.5* 106cells / kg. In an embodiment, the first dose is administered to the subj ect at a concentration of about 2.85 * 106cells / kg. In an embodiment, the first dose comprises a concentration of about 3*106cells / kg. In an embodiment, the first dose comprises a concentration of about 5 * 106cells / kg. In an embodiment, the first dose is administered to the subject at a concentration of about 30* 106cells / kg. In an embodiment, the first dose is administered to the subject at a concentration of about 50* 106c...

Claims

1. WSGR Ref. No.: 64320-710.601CLAIMSWhat is claimed:

1. A method of treating a dystrophinopathy in a subject in need thereof, comprising administering allogeneic, human, neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (an nMPC conditioned medium), nMPC exosomes, or any combination thereof, whereby the dystrophinopathy is treated.

2. A method of treating cardiomyopathy associated with a dystrophinopathy in a subject in need thereof, comprising administering allogeneic, human, neonatal cardiac mesenchymal progenitor cells (nMPCs), an nMPC secretome (an nMPC conditioned medium), nMPC exosomes, or any combination thereof, whereby the cardiomyopathy is treated.

3. The method of claim 1 or 2, wherein the cardiomyopathy is dilated cardiomyopathy (DCM).

4. The method of any one of the preceding claims, wherein the subject is administered the nMPCs.

5. The method of any one of the preceding claims, wherein a dose of the nMPCs comprises from about 15 million to about 250 million nMPCs.

6. The method of any one of the preceding claims, wherein a dose of the nMPCs comprises from about 35 million to about 65 million nMPCs.

7. The method of any one of the preceding claims, wherein a dose of the nMPCs comprises from about 45 million to about 55 million nMPCs.

8. The method of any one of the preceding claims, wherein a dose of the nMPCs comprises about 50 million nMPCs.

9. The method of any one of claims 1-5, wherein a dose of the nMPCs comprises from about 85 million to about 115 million nMPCs.

10. The method of claim 9, wherein a dose of the nMPCs comprises from about 95 million to about 105 million nMPCs.

11. The method of claim 9 or 10, wherein a dose of the nMPCs comprises about 100 million nMPCs.

12. The method any one of claims 1-5, wherein a dose of the nMPCs comprises from about 135 million to about 165 million nMPCs.

13. The method of claim 12, wherein a dose of the nMPCs comprises from about 145 million to about 155 million nMPCs.

14. The method of claim 12 and 13, wherein a dose of the nMPCs comprises about 150 million nMPCs.

15. The method of any one of claims 1-5, wherein a dose of the nMPCs comprises from about 185 million to about 215 million nMPCs.

16. The method of claim 15, wherein a dose of the nMPCs comprises from about 195 million to about 205 million nMPCs.

17. The method of claim 15 or 16, wherein a dose of the nMPCs comprises about 200 million nMPCs.WSGR Ref. No.: 64320-710.60118. The method of any one of claims 1-5, wherein a dose of the nMPCs comprises from about 235 million to about 265 million nMPCs.

19. The method of claim 18, wherein a dose of the nMPCs comprises from about 245 million to about 255 million nMPCs.

20. The method of claim 18 or 19, wherein a dose of the nMPCs comprises about 250 million nMPCs.

21. The method of any one of the preceding claims, wherein a dose of the nMPCs is administered to the subject at a concentration of from about 0.5 / IO6nMPCs per kilogram of subject body weight (cells / kg or nMPCs / kg) to about 2.5* 108nMPCs / kg.

22. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of from about 0.5 / IO6cells / kg to about 2.5 / IO6cells / kg.

23. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of from about 5 / IO6cells / kg to about 2.5 / IO8cells / kg.

24. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 0.5 / IO6cells / kg.

25. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 0.625 / IO6cells / kg.

26. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 0.7 / IO6cells / kg.

27. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 1.0 / 106cells / kg.

28. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 1.25 / IO6cells / kg.

29. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 1.43 / IO6cells / kg.

30. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 2.5 / IO6cells / kg.

31. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 2.85 / IO6cells / kg.

32. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 3 / IO6cells / kg.

33. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 5.0 / IO7cells / kg.

34. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 2.0 / IO8cells / kg.

35. The method of claim 21, wherein a dose of the nMPCs is administered to the subject at a concentration of about 2.5 / IO8cells / kg.WSGR Ref. No.: 64320-710.60136. The method of any one of the preceding claims, wherein a symptom of dystrophinopathy is improved by 2% or more, or by 2-fold or more, following treatment as compared to treatment with a placebo or compared to the subject prior to treatment.

37. The method of any one of the preceding claims, wherein nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a.

38. The method of any one of the preceding claims, wherein the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2.

39. The method of any one of the preceding claims, wherein the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2.

40. The method of any one of the preceding claims, wherein the nMPCs are further negative for protein expression of pl6INK4aup to at least passage 8.

41. The method of any one of the preceding claims, wherein the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, or SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, or pl6INK4a.

42. The method of any one of the preceding claims, wherein the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

43. The method of any one of the preceding claims, wherein the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p.

44. The method of any one of the preceding claims, wherein the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and / or PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p.WSGR Ref. No.: 64320-710.60145. The method of any one of the preceding claims, wherein the nMPCs are (a) positive for protein expression of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p, (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a, and (e) genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p.

46. The method of any one of the preceding claims, wherein the nMPCs are allogeneic or autologous.

47. The method of any one of the preceding claims, wherein the nMPCs are non-naturally occurring.

48. The method of any one of the preceding claims, wherein the nMPCs are not xenogenic.

49. The method of any one of the preceding claims, wherein the nMPCs are obtained from a subject who is biologically a female.

50. The method of any one of the preceding claims, wherein the nMPCs are obtained from a subject who is biologically a male.

51. The method of any of the preceding claims, wherein the subject is administered the nMPC secretome.

52. The method of claim 51, wherein the nMPC secretome is (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p.

53. The method of claim 51 or 52, wherein the nMPC secretome is (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p.

54. The method of any one of claims 51-53, wherein the nMPC secretome is positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of FUS, TAF15, CAP2, SNX9, PSMB7, SUMO1, EIF3A, ECHI, HNRNPL, NTM, ANG, ERP44, NAA38, RRM2B, RAB1A, RAB1B, PGRMC1, ERH, TIGAR, ITGA2, SGTA, AR1C1, AKR1C2, DNASE2, HSP90AB4P, ANGPTL2, SF3B2, GREM1, ARF3, ARF1, ARF5, LSM5, PSMD9, SUGT1, ALDH1A3, PDGFRB, HIST1H1C, SP100, G6PD, PPIL1, SNRPD1, FDPS, RAB6B, RAB6A, DCTD, GLB1, ARIH1, IST1, HNRNPU, ULBP2, RAET1G, ERAP2, CDC42, EDF1, LIPG, FKBP4, RBMX, RBMXL1, RPL30, THY1, AP2M1, RPS16, FHL3, BZW1, BZW2, EIF4G1, PFDN4, CLTB, PIR, MVP, ECU, DCI, ALYREF, RPS10, PPP3CA, TAX1BP3, PPA1, DDX39B, DDX39A, GNPNAT1, LIMA1, SNRPD3, ADH5, ENAH, DYNLL1, DYNLL2, HUWE1, HMGB2, PTMS, UCHL3, PFDN2, DYNLRB1, HDGFRP2, INF2, HPRT1, EIF2S2, ADAMT7, EIF3C, EIF3CL, RPS5, VPS35, CS, ECHS1, UBQLN1, GBP2, GBP1, SF3B1, RANBP1, GNS, HLA-B, UBXN1, GNPDA1, IGF2, EIF3B, TCEB1, VASP, GSR, HLA-A, HLA-HIGF2, NUDT5, COPE, HNRNPA3, SRI, HNRNPC, MMP10, EWSR1, IPO7, YARS,WSGR Ref. No.: 64320-710.601TMPO, HNRNPH1, HLA-A, PDGFC, IL1B, S100A10, TXNDC2, DPY30, LAMP1, LYPLA1, CBR1, ARHGAP1, TPR, NAMPT, NAMPTL, CXCL2, EIF4A2, RPS4X, PABPN1, PHLDB1, NAP1L4, DDX6, PSMC3, MAP7D1, OSCAR, TES, NMT1, NMT2, MAT2A, PRMT1, COX17, SELM, CARS, PPP2CA, PPP2CB, VEGFC, VPS26A, PXN, PAWR, STRAP, RAB11A, RAB11B, EIF5, COPZ1, COPS3, CHMP4B, PDXK, RALA, RALB, SEC13, FHL2, TOM1, PYCARD, PDLIM4, RBBP4, RBBP7, RPS20, SRSF1, DLD, SNRPE, EIF4EBP1, RPLPO, RPLP0P6, LSM3, SLC16A3, CSE1L, NUCKS1, TSNAX, RPSA, RPSAP58, AP1B1, EIF2S1, LCP1, PSMD4, AARS, SRSF2, SFRS2, TRIP10, CLTA, USO1, VBP1, UBE2K, MRPL12, UAP1, HIST1H1B, YBX3, RPL10A, IDH1, SNRPN, SNRPB, PCK2, EIF6, MMP3, DHX9, MATR3, UBE2D2, UBE2D3, PTRF, ACTR1A, LAMA1, PDCD6IP, QARS, HN1L, PLBD2, OS9, ILF3, ISOC1, PPP1R7, MAPK1, PDCD1LG2, GOLGB1, HSPA9, ACBD3, BTF3, UBE2I, SRRT, EIF4H, FERMT2, EIF3G, PARVA, DBNL, BOLA2, MAPRE1, PRDX5, STX12, EIF1, SMS, GRPEL1, OAF, SYNCRIP, ECE1, VAPA, PCNP, PSME1, EIF3J, C14orfl66, DDX1, AKR1B1, SRP9, PCMT1, XPO1, MMP9, RPS7, NRCAM, FKBP3, SSB, DSC3, XRCC5, CCT6A, LIF, SERPINA9, SND1, ANP32B, G3BP1, GPC6, GLOD4, RRBP1, TGFB1, USP14, PLAUR, CXCL3, FASN, COPB2, TARDBP, TNFAIP6, RPS3, NDUFAB1, LMNB1, COL16A1, PSMF1, PHGDH, PRKCDBP, CXCL5, YAP1, TROVE2, MACF1, EIF5B, STX7, PFDNS, APOA1, PDAP1, STX12, EIF3K, FH, RBM8A, EIF1, RPS2, PTGR1, EEA1, CAB39, DCTN2, GDF15, MYL9, TCP1, RPS12, RAD23A, SKP1, PDLIM1, HSPH1, PSMB3, SUB1, API5, TWF2, KTN1, DYNC1H1, SNRNP70, MCFD2, PPP1R18, PTGES3, APEX1, TNKS1BP1, FUBP1, VAT1, PAFAH1B1, CBX1, PTK7, HNRPDL, ZNF185, DYNC1I2, KHDRBS1, SFPQ, PDCD5, TRIM28, PPIC, NARS, PCBP2, CD2AP, PSMA1, CAPRIN1, KHSRP, NSFL1C, PPP1R12A, NUDC, MFAP2, IGF2R, RGMB, PABPC1, MAN1A1, DDB1, PTBP1, FBN2, CNBP, OTUB1, NASP, HSPD1, EEF1D, RNPEP, CRKL, HNRNPAB, EIF3F, PAICS, ILF2, COPB1, PA2G4, COPA, NT5E, HMGA1, SF1, XRCC6, GNB2L1, MEI, MTAP, CCT2, ARCN1, PEPD, and EPB41L3.

55. The method of any one of claims 51-54, wherein the nMPC secretome is positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of PPP1CA, PPP1CC, ST13, ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, NEDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1, NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, ENO1, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPA0, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, 42254, and PAFAH1B2.

56. The method of any one of claims 51-54, wherein the nMPC secretome is positive for protein expression of one, two, three, four, five, six, seven, eight, nine, ten, or more of PPP1CA, PPP1CC, ST13, ST13P5, ST13P4, HMGB1, HMGB1P1, HNRNPA1, HNRNPA1L2, NEDD8, NEDD8-MDP1, YBX1, YBX2, CCT7, HNRNPH3, LTBP1, UBE2N, IL8, CYCS, LGALS1, IL6, PGAM1, YWHAH, TXN, ARHGDIB, PSMA3, RAN, TPM3, BASP1, HSPA8, ITGAV, PPIA, NACA, HSP90AB1, PCBP1, CAP1,WSGR Ref. No.: 64320-710.601NUTF2, PSMA5, CAPZA1, RPLP1, GLO1, ACTG1, ICAM1, SDC4, SOD2, PSMB4, TFPI2, C1QBP, NAP1L1, HSP90AA1, SET, ENO1, CCT3, GOT2, HSPE1, PGM3, PLIN3, CNDP2, PGD, SH3BGRL, TLN1, HSP90AB2P, GOT1, HNRNPA0, FTH1, TPD52L2, UGP2, AHNAK, CCT8, PSMA7, CCT4, SRPX2, CLIC4, KPNB1, AP2B1, and PAFAH1B2.

57. The method of any of the preceding claims, wherein the subject is administered the nMPC exosomes.

58. The method of claim 57, wherein the nMPC exosomes are positive for protein expression of are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p.

59. The method of claim 57 or 58, wherein the nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p.

60. The method of any one of claims 57-59, wherein the nMPC exosomes are positive for expression of CD81 and / or CD63.

61. The method of any one of claims 57-60, wherein the nMPC exosomes are negative for protein expression of IGF1.

62. The method of any one of the preceding claims, wherein administration is intravenous (IV) injection, or intravenous (IV) catheter (e.g., intravenous (IV) infusion).

63. The method of any one of the preceding claims, wherein the nMPCs are administered by intravenous infusion.

64. The method of claim 63, wherein the nMPCs are infused via IV catheter for from about 35 minutes to about 180 minutes, from about 40 minutes to about 90 minutes, from about 55 minutes to about 65 minutes, or about 60 minutes.

65. The method of any one of the preceding claims, wherein the nMPCs are administered into the heart of the subject via intramyocardial transplantation.

66. The method of any one of the preceding claims, wherein the subject to be treated is a carrier of a genetic mutation that causes a muscular dystrophy.

67. The method of any one of the preceding claims, wherein the nMPCs are negative for a mutation known to be causative of a dystrophinopathy.

68. The method of claim 66 or 67, wherein the muscular dystrophy comprises a hereditary muscular dystrophy, an acquired muscular dystrophy, or an intermediate phenotype muscular dystrophy.

69. The method of any one of claims 66-68, wherein the muscular dystrophy is a Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), a limb-girdle muscular dystrophy (LGMD), a congenital muscular dystrophy, a congenital myopathy, a distal hereditary myopathy, a facioscapulohumeral muscular dystrophy (FSHD), an oculopharyngeal muscular dystrophy (OPMD), Emery-Dreifuss muscular dystrophy (EDMD), a congenital muscular dystrophy, a Congenital myopathy,WSGR Ref. No.: 64320-710.601a Myofibrillar myopathy, an Inclusion body myositis (IBM), a myotonic dystrophy, a metabolic myopathy, a mitochondrial myopathy, or an inflammatory myopathy.

70. The method of any one of the preceding claims, wherein the dystrophinopathy comprises Duchenne muscular dystrophy (DMD).

71. The method of any one of the preceding claims, wherein the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising DMD.

72. The method of claim 71, wherein the mutation is in a gene encoding dystrophin.

73. The method of claim 72, wherein the gene is in a Xp21.2 chromosome.

74. The method of any one of claims 66-73, wherein the mutation is an out-of-frame mutation of a dystrophin gene open reading frame, and the out-of-frame mutation causes a lack of dystrophin expression.

75. The method of any one of claims 66-74, wherein the nMPCs comprise a wild-type dystrophin gene encoding a functional dystrophin protein.

76. The method of any one of claims 1-69, wherein the dystrophinopathy comprises Becker muscular dystrophy (BMD).

77. The method of claim 76, wherein the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising Becker muscular dystrophy.

78. The method of claim 77, wherein the mutation is in a gene encoding dystrophin.

79. The method of claim 78, wherein the gene is in a Xp21.2 chromosome.

80. The method of any one of claims 76-79, wherein the mutation is an in-frame mutation, and the in-frame mutation causes dystrophin deficiency or dysfunction.

81. The method of any one of claims 76-80, wherein the nMPCs comprise a wild-type dystrophin gene encoding a functional dystrophin protein.

82. The method of any one of claims 1-69, wherein the dystrophinopathy comprises an Emery -Dreifuss muscular dystrophy.

83. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a myotonic muscular dystrophy.

84. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a facioscapulohumeral muscular dystrophy (FSMD).

85. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a congenital muscular dystrophy.

86. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a limb-girdle muscular dystrophy (LGMD).

87. The method of any one of claims 1-69, wherein the dystrophinopathy comprises an oculopharyngeal muscular dystrophy.

88. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a congenital muscular dystrophy.WSGR Ref. No.: 64320-710.60189. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a congenital myopathy.

90. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a myofibrillar myopathy.

91. The method of any one of claims 1-69, wherein the dystrophinopathy comprises an inclusion body myositis (IBM).

92. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a myotonic dystrophy.

93. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a metabolic myopathy.

94. The method of any one of claims 1-69, wherein the dystrophinopathy comprises a mitochondrial myopathy.

95. The method of any one of claims 1-69, wherein the dystrophinopathy comprises an inflammatory myopathy.

96. The method of any one of claims 1-69, wherein the dystrophinopathy comprises X-linked cardiomyopathy (or DMD-associated dilated cardiomyopathy (DCM)).

97. The method of claim 96, wherein the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising X-linked cardiomyopathy (or DMD-associated dilated cardiomyopathy (DCM)).

98. The method of claim 97, wherein the mutation is in a gene encoding dystrophin.

99. The method of claim 98, wherein the gene is in a Xp21.2 chromosome.

100. The method of any one of claims 97-99, wherein the mutation is an in-frame mutation, and the in-frame mutation causes dystrophin deficiency or dysfunction.

101. The method of any one of claims 97-100, wherein the nMPCs comprise a wild-type dystrophin gene encoding a functional dystrophin protein.

102. The method of any one of claims 1-101, wherein the method comprises treating cardiomyopathy in a subject diagnosed with a dystrophinopathy.

103. The method of any one of claims 1-101, wherein the nMPCs are administered to the subject once every 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 days.

104. The method of any one of claims 1-101, wherein the nMPCs are administered to the subj ect once every twenty-eight (28) ±3 days, once every 45±3 days, once every 54±3 days, once every 60±3 days, once every 70±3 days, once every 80±3 days, once every 90±3 days, or once every 100±3 days.

105. The method of any one of the preceding claims, wherein the nMPCs are administered to the subject for from about 1 month to about 100 years.

106. The method of any one of the preceding claims, wherein motor neuron function improves by at least 2% following treatment compared to a placebo or compared to the subject prior to treatment.WSGR Ref. No.: 64320-710.601107. The method of any one of the preceding claims, wherein muscle loss is inhibited or slowed at least 2% following treatment compared to a placebo or compared to the subject prior to treatment.

108. The method of any one of the preceding claims, wherein muscle weakness is inhibited or slowed at least 2% following treatment compared to a placebo or compared to the subject prior to treatment.

109. The method of any one of the preceding claims, wherein the administration of the nMPCs results in improved cardiac function, muscle regeneration, increased muscle strength, increased flexibility, increased range of motion, increased stamina, reduced fatigability, increased blood flow, improved cognition, improved pulmonary function, inflammation inhibition, reduced muscle fibrosis, reduced muscle necrosis, improved muscle fibrosis, improved swallowing, improved bowel and bladder function, improved cognitive function, improved behavior, improved socialization, improved respiration, or a combination thereof.

110. The method of any one of the preceding claims, wherein a symptom to be treated is muscle wasting, muscle weakness, muscle fragility, muscle necrosis, muscle fibrosis, joint contracture, skeletal deformation, cardiomyopathy, impaired swallowing, impaired bowel and bladder function, muscle ischemia, cognitive impairment, behavioral dysfunction, socialization impairment, scoliosis, or impaired respiratory function.

111. The method of any one of the preceding claims, wherein a symptom to be treated is stiffness of joints, wasting or weakening of muscles (e.g, muscles in the shoulders, upper arms and calves), heart conditions (e.g., palpitations, presyncope, syncope, poor exercise tolerance, congestive heart failure, variable cardiac rhythm disturbances, bradycardia, atrial ventricular conduction defects, heart blockage, ventricular myocardial disease with failure and stroke, secondary to cardiac arrhythmia etc. ), fainting, an awkward gait, a tendency for toe walking, fixed equinus deformities of the ankles, flexion contractures of the elbows, extension contracture of the neck, tightness of the lumbar paravertebral muscles, respiratory insufficiency, muscle wasting (e.g., of biceps, triceps, clavicular head of the pectoral muscles, abdomen, ankles, tibialis anterior muscle, etc.), restrictive lung disease, intellectual disability, epilepsy, facial weakness, delayed motor milestones, progressive limb-girdle pattern of weakness, marked muscle wasting, hyperlordosis, loss of ambulation, ptosis, head drop, joint contractures, cardiomyopathy, weakness of the orbicularis oris muscle, limited facial expression, transverse smile, incomplete burying of eyelashes, forced eye closure, scapular winging, hearing loss, retinal vasculopathy (Coats disease), retinal detachment, blindness, progressive muscle wasting, atrophy of myocytes (affecting the eye and periocular muscles), extraocular muscle weakness, ptosis, disruptive eye movements dysphagia, impaired swallow efficiency, reduced pharyngeal constriction, reduced speed of hyoid movement, airway closure, oral regurgitation, nasal regurgitation, aspiration, post-swallow pharyngeal residue, esophageal retention, difficulty swallowing, weight loss, malnutrition, aspiration, facial weakness, hip weakness, shoulder weakness, change in voice quality, excessive fatigue, impaired cognitive function, extreme emaciation starvation, death, muscle weakness (distal and facial weakness of arms, hands, ankles, jaw, tongue or neck flexors), myotonia (often affecting the hands, tongue and jaw due to slow muscle relaxation), distal progressive muscle wasting, distal progressive muscle weakness, facial involvement, bulbar involvement,WSGR Ref. No.: 64320-710.601high palate, dysphonia, chronic pain (e.g, of the hands and feet), small fiber neuropathy, large fiber neuropathy, an increased risk for benign tumors, an increased risk for malignancies, and higher complications of adverse reactions to anesthesia and analgesic drugs relative to the general population, progressive cognitive decline, changes in brain white matter, fatigue, droopy eyelids, handshaking, breathing difficulties, swallowing difficulties, congenital hypotonia, delayed motor development, progressive muscle weakness, weak cry, poor feeding, weak muscle tone (hypotonia), damaged muscle fibers, atrophy of the skeletal muscles, weakness of the facial muscles, droopy eyelids (ptosis), an open mouth, joint deformities (contractures), impaired brain development, cobblestone lissencephaly, delayed development of speech and motor skills, moderate to severe intellectual disability, impaired social skills, seizures, impaired vision, eye abnormalities, progressive heart problems, swallowing difficulties, aspiration pneumonia, deterioration (atrophy) of skeletal muscles (limb-girdle muscle deterioration), late-onset distal myopathy (affecting ankles, feet or calves), respiratory insufficiency, cardiac failure, cardiac arrhythmia, skeletal muscle weakness due to impaired mitochondrial form and function, muscle rippling, myalgia, HyperCKemia, ankle contracture, calf hypertrophy, exercise intolerance, muscular cramps, fat infiltration, increased number of internal nuclei and rimmed vacuoles, cardiomyopathy, fatty replacement in semitendinosus, gastrocnemius and soleus, distal weakness, facial weakness, bulbar weakness, a pelvic lower girdle weakness, atrophy of the axial muscle and shoulder girdle, fatty replacement of fibers in pelvic and thigh muscles, cognitive impairment, decrease in a-dystroglycan glycosylation, myopia, epilepsy, cataracts, or a combination thereof.

112. The method of claim 110 or 111, wherein a symptom is improved by 2% or more following treatment compared to a placebo or compared to the subject prior to treatment.

113. The method of any one of the preceding claims, wherein the method further comprises administering to the subject one or more additional therapeutic agent(s).

114. The method of claim 113, wherein the one or more additional therapeutic agent(s) comprise(s) an aldosterone antagonist, an angiotensin-converting enzyme inhibitor (ACEi), an angiotensin receptor blocker (ARB), a beta blocker, a blood thinner, a cardiac glycoside, a diuretic, a biguanide, a statin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a glucagon- 1 receptor agonist, a corticosteroid, an exon-skipping therapy, an AAV-based gene therapy, a HD AC inhibitor, or a combination thereof.

115. The method of any one of the preceding claims, wherein the subject is a mammal.

116. The method of claim 115, wherein the mammal is a human.

117. The method of claim 116, wherein the human is a child of from birth to 18 years of age.

118. The method of claim 116, wherein the human is an adult of over 18 years of age.

119. The method of claim 116, wherein the human is from about 4 years of age to about 30 years of age or from about 4 years of age to about 18 years of age.

120. The method of claim 116, wherein the human is from about 18 years of age to about 30 years of age.

121. The method of any one of the preceding claims, wherein the subject is screened or monitored at one or more times prior to treatment, during treatment, and / or after treatment.WSGR Ref. No.: 64320-710.601122. The method of claim 121, wherein screening comprises a physical evaluation, medical history review, and one or more diagnostic tests.

123. The method of claim 121 or 122, wherein the one or more diagnostic tests comprise(s) ) genetic testing (e.g., DMD gene deletion-duplication analysis, Sanger DNA sequencing, Next-generation DNA sequencing, RNA sequencing, etc.), immunohistochemical analyses (e.g, analysis of muscle biopsy cryosections, immunoblots), biochemical analyses (e.g, protein truncation tests, PCR, etc.), and / or blood tests (e.g, detection of elevated Creatine Kinase (CK) levels, etc.).

124. The method of any one of the preceding claims, wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 28±3, wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 45+3, wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 54+3, wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 60±3, or wherein the subject is administered a first dose of the nMPCs at day 0 and a second dose of the nMPCs at day 90±3.

125. The method of any one of the preceding claims, wherein the subject is assessed at day 7 or about every 7 days following treatment.

126. The method of any one of the preceding claims, wherein one or more proinflammatory cytokines in the subj ect are reduced by at least 2% compared to treatment with a placebo or compared to the subj ect prior to treatment.

127. The method of claim 126, wherein the one or more proinflammatory cytokines comprise IL-8, IL-17A, MCP-1, or a combination thereof.

128. The method of any one of the preceding claims, wherein one or more anti-inflammatory cytokines in the subject are increased by at least 2% compared to treatment with a placebo or compared to the subject prior to treatment.

129. The method of claim 128, wherein the one or more anti-inflammatory cytokines comprise IL-10.

130. The method of any one of the preceding claims, wherein the subject has an improved quality of life following treatment compared to treatment with a placebo or compared to the subject prior to treatment.

131. The method any one of claims 1-127, wherein the subject is biologically a male.

132. The method any one of claims 1-131, wherein the subject is biologically a female.

133. The method any one of the preceding claims, wherein the subject is from about 1 to about 10 years of age, from about 4 to about 18 years of age, from about 11 to about 20 years of age, from about 21 to about 30 years of age, from about 31 to about 40 years of age, from about 51 to about 60 years of age, from about 71 to about 80 years of age, from about 81 to about 90 years of age, or about 91+ years of age.

134. The method of any one of the preceding claims, wherein the nMPCs are stable in storage at a temperature for a period of time.WSGR Ref. No.: 64320-710.601135. The method of claim 134, wherein the temperature is about 4 °C, 1 °C, 0 °C, -10 °C, -20 °C, or -80 °C.

136. The method of claim 134 or 135, wherein the period of time is at least about 1, 2, 3, 4, 5, 6, or 7 days; at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks; or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months.

137. The method of any one of claims 134-136, wherein the nMPCs are stored in cell cryopreservation media-CS10 (CRYOSTOR®; Sigma- Aldrich, Israel).

138. The method of any one of claims 134-137, wherein the nMPCs are thawed in a 37 °C water bath until a single ice crystal remained prior to administration to the subject.

139. The method of claim 138, wherein the nMPCs are further washed with a volume of Complete Medium (CM).

140. The method of claim 138, wherein the nMPCs are washed twice with a volume of Complete Medium (CM).

141. The method of claim 139 or 140, wherein the volume is at least about 10 ml.

142. The method of any one of the preceding claims, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2;(b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1;(c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR- 3613-5p, miR-582-3p, miR-7641, and miR-374b-5p,(d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4; and / or(e) negative for protein expression of pl6INK4aup to at least passage 8.

143. The method of any one of the preceding claims, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2;(b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1;(c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR- 3613-5p, miR-582-3p, miR-7641, and miR-374b-5p; and(d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

144. The method of any one of claims 1-143, wherein the nMPC secretome does not comprise 42254.

145. A composition comprising allogeneic, human nMPCs, wherein the nMPCs are (a) positive for protein expression of Ki67 orNkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117),WSGR Ref. No.: 64320-710.601CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or p16INK4a146. The composition of claim 145, wherein the nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, and / or SOX2.

147. The composition of claim 145 or 146, wherein the nMPCs are further negative for protein expression of pl6INK4aup to at least passage 8.

148. The composition of any one of claims 145-147, wherein the composition further comprises the nMPC secretome or nMPC exosomes.

149. The composition of any one of claims 145-148, wherein the composition comprises a Total nMPC secretome comprising the nMPC secretome and nMPC exosomes.

150. The composition of claim 148 or 149, wherein the nMPC secretome or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and / or Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p.

151. The composition of any one of claims 148-150, wherein the nMPC secretome or nMPC exosomes are (a) positive for protein expression of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, HSF1, and Akt, and (b) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p.

152. The composition of any one of claims 148-151, wherein the nMPC secretome or exosomes are negative for protein expression of IGF 1.

153. The composition of any one of claims 148-152, wherein the nMPCs are genetically engineered.

154. The composition of claim 153, wherein the nMPCs are genetically engineered to overexpress one or more paracrine factors.

155. The composition of claim 153 or 154, wherein the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, or miR-374b-5p.

156. The composition of claim 155, wherein the nMPCs are genetically engineered to overexpress HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p.

157. The composition of claim 155, wherein the nMPCs are genetically engineered to overexpress 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 of HGF, SCF, SDF-la, ANG1, VEGFA, PDGFB, bFGF, HSP20, Akt, miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and miR-374b-5p.

158. The composition of any one of claims 145-157, wherein the nMPCs are non-naturally occurring.

159. The composition of any one of claims 145-158, wherein the nMPCs are not xenogenic.

160. The composition of any one of claims 145-159, wherein the nMPCs are (a) positive for protein expression of Ki67 and Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-WSGR Ref. No.: 64320-710.6013613-5p, miR-582-3p, miR-7641, and miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and p16INK4a161. The composition of any one of claims 145-160, wherein the nMPC secretome or exosomes are positive for protein expression of one or more of the proteins in Table 7.

162. The composition of any one of claims 145-161, wherein the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising DMD.

163. The composition of claim 162, wherein the mutation is in a gene encoding dystrophin.

164. The composition of claim 163, wherein the gene is in a Xp21.2 chromosome.

165. The composition of any one of claims 162-164, wherein the mutation is an out-of-frame mutation of a dystrophin gene open reading frame, and the out-of-frame mutation causes a lack of dystrophin expression.

166. The composition of any one of claims 162-165, wherein the nMPCs comprise a wild-type dystrophin gene encoding a functional dystrophin protein.

167. The composition of any one of claims 162-166, wherein the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising Becker muscular dystrophy.

168. The composition of claim 167, wherein the mutation is in a gene encoding dystrophin.

169. The composition of claim 168, wherein the gene is in a Xp21.2 chromosome.

170. The composition of any one of claims 167-169, wherein the mutation is an in-frame mutation, and the in-frame mutation causes dystrophin deficiency or dysfunction.

171. The composition of any one of claims 145-161, wherein the nMPCs are negative for a mutation known to be causative of a dystrophinopathy comprising X-linked cardiomyopathy (or DMD-associated dilated cardiomyopathy (DCM)).

172. The composition of claim 171, wherein the mutation is in a gene encoding dystrophin.

173. The composition of claim 172, wherein the gene is in a Xp21.2 chromosome.

174. The composition of any one of claims 171-173, wherein the mutation is an in-frame mutation, and the in-frame mutation causes dystrophin deficiency or dysfunction.

175. The composition of any one of claims 171-174, wherein the nMPCs comprise a functional dystrophin gene.

176. The composition of any one of claims 145-175, wherein the nMPCs are obtained from a subject who is biologically a female.

177. The composition of any one of claims 145-175, wherein the nMPCs are obtained from a subject who is biologically a male.

178. The composition of any one of claims 145-177, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2;(b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1;WSGR Ref. No.: 64320-710.601(c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR- 3613-5p, miR-582-3p, miR-7641, and miR-374b-5p,(d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4; and / or(e) negative for protein expression of pl6INK4aup to at least passage 8.

179. The composition of any one of claims 145-178, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2;(b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1;(c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR- 3613-5p, miR-582-3p, miR-7641, and miR-374b-5p; and(d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

180. A composition comprising cryopreserved, allogeneic, human nMPCs, wherein the cryopreserved, allogeneic, human nMPCs are (a) positive for protein expression of Ki67 or Nkx2.5, (b) positive for cell surface protein expression of c-Kit (CD117), CD44, CD73, CD47, CD105, and / or CD90, (c) positive for miRNA expression of miR-31-3p, miR-31-5p, miR-3613-5p, miR-582-3p, miR-7641, and / or miR-374b-5p, and (d) negative for protein expression of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and / or pl6INK4a.

181. The composition of claim 180, wherein the cryopreserved, allogeneic, human nMPCs are further positive for protein expression of PDL1, OCT3 / 4, NANOG, KLF4, HSF1, and / or SOX2.

182. The composition of claim 180 or 181, wherein the cryopreserved, allogeneic, human nMPCs are further negative for protein expression of pl6INK4aup to at least passage 8.

183. The composition of any one of claims 180-182, wherein the composition further comprises cryopreserved conditioned medium or exosomes.

184. The composition of claim 183, wherein the composition further comprises cryopreserved conditioned medium and cryopreserved exosomes.

185. The composition of any one of claims 180-184, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2;(b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1;(c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR- 3613-5p, miR-582-3p, miR-7641, and miR-374b-5p,(d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, or 9 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, and SSEA4; and / or(e) negative for protein expression of pl6INK4aup to at least passage 8.WSGR Ref. No.: 64320-710.601186. The composition of any one of claims 180-185, wherein the nMPCs are:(a) positive for protein expression of 1, 2, 3, 4, 5, 6, or 7 of Ki67, Nkx2.5, OCT3 / 4, NANOG, KLF4, HSF1, and SOX2;(b) positive for cell surface protein expression of 1, 2, 3, 4, 5, 6, or 7 of c-Kit (CD117), CD44, CD73, CD47, CD105, CD90, and PDL1;(c) positive for miRNA expression of 1, 2, 3, 4, 5, or 6 of miR-31-3p, miR-31-5p, miR- 3613-5p, miR-582-3p, miR-7641, and miR-374b-5p; and(d) negative for protein expression of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 of CD34, CD45, CD31, PECAM-1, tryptase, GATA4, ISL1, SSEA3, SSEA4, and pl6INK4a.

187. The composition of any one of claims 180-186, wherein the nMPCs do not express 42254.

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