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1664-042X142023Frontiers in physiologyFront PhysiolDuchenne muscular dystrophy: disease mechanism and therapeutic strategies.11831011183101118310110.3389/fphys.2023.1183101Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. The identification of the dystrophin gene as central to DMD pathogenesis has led to the understanding of the muscle membrane and the proteins involved in membrane stability as the focal point of the disease. The lessons learned from decades of research in human genetics, biochemistry, and physiology have culminated in establishing the myriad functionalities of dystrophin in striated muscle biology. Here, we review the pathophysiological basis of DMD and discuss recent progress toward the development of therapeutic strategies for DMD that are currently close to or are in human clinical trials. The first section of the review focuses on DMD and the mechanisms contributing to membrane instability, inflammation, and fibrosis. The second section discusses therapeutic strategies currently used to treat DMD. This includes a focus on outlining the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, repair, and/or a range of dystrophin-independent approaches. The final section highlights the different therapeutic strategies for DMD currently in clinical trials.Copyright © 2023 Bez Batti Angulski, Hosny, Cohen, Martin, Hahn, Bauer and Metzger.Bez Batti AngulskiAddeliADepartment of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.HosnyNoraNDepartment of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.CohenHoudaHDepartment of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.MartinAshley AAADepartment of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.HahnDongwooDDepartment of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.BauerJackJDepartment of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.MetzgerJoseph MJMDepartment of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, United States.engR01 AR079477ARNIAMS NIH HHSUnited StatesR01 HL132874HLNHLBI NIH HHSUnited StatesJournal ArticleReview20230626
SwitzerlandFront Physiol1015490061664-042XDuchenne muscular dystrophydystrophinmuscle diseasepathophysiologyskeletal muscletherapeutic strategiesJM is on the scientific advisory board of and holds shares in Phrixus Pharmaceuticals Inc., a company developing novel therapeutics for heart failure. The terms of this arrangement have been reviewed and approved by the University of Minnesota in accordance with its conflict-of-interest policies.20233920235242023712643202371264220237123562023626epublish37435300PMC1033073310.3389/fphys.2023.11831011183101Aartsma-Rus A., Ferlini A., Goemans N., Pasmooij A. M., Wells D. J., Bushby K., et al. (2014). Translational and regulatory challenges for exon skipping therapies. Hum. Gene Ther. 25, 885–892. 10.1089/hum.2014.08610.1089/hum.2014.08625184444Aartsma-Rus A., Fokkema I., Verschuuren J., Ginjaar I., van Deutekom J., van Ommen G. J., et al. (2009). Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum. Mutat. 30, 293–299. 10.1002/humu.2091810.1002/humu.2091819156838Aartsma-Rus A., van Putten M. (2020). The use of genetically humanized animal models for personalized medicine approaches. Dis. Model Mech. 13, dmm041673. 10.1242/dmm.04167310.1242/dmm.041673PMC690663031591145Aartsma‐Rus A., Van Deutekom J. C. T., Fokkema I. F., Van Ommen G. B., Den Dunnen J. T. (2006). Entries in the leiden duchenne muscular dystrophy mutation database: An overview of mutation types and paradoxical cases that confirm the reading‐frame rule. Muscle and Nerve Official J. Am. Assoc. Electrodiagn. Med. 34, 135–144. 10.1002/mus.2058610.1002/mus.2058616770791Abmayr S., Chamberlain J. (2006). The structure and function of dystrophin. Molecular mechanisms of muscular dystrophies. Georget. Landes Biosci., 14–34.Adams-Graves P., Kedar A., Koshy M., Steinberg M., Veith R., Ward D., et al. (1997). RheothRx (poloxamer 188) injection for the acute painful episode of sickle cell disease: A pilot study. Blood 90, 2041–2046. 10.1182/blood.V90.5.204110.1182/blood.V90.5.20419292541 Ahmad M., Wolberg A., Kahwaji C. I. (2022). “Biochemistry, electron transport chain,” in StatPearls (treasure island (FL).30252361Ahn A. H., Kunkel L. M. (1993). The structural and functional diversity of dystrophin. Nat. Genet. 3 (4), 283–291. 10.1038/ng0493-28310.1038/ng0493-2837981747Allen D. G., Whitehead N. P., Froehner S. C. (2016). Absence of dystrophin disrupts skeletal muscle signaling: Roles of Ca2+, reactive oxygen species, and nitric oxide in the development of muscular dystrophy. Physiol. Rev. 96, 253–305. 10.1152/physrev.00007.201510.1152/physrev.00007.2015PMC469839526676145Amin R. S., Kimball T. R., Bean J. A., Jeffries J. L., Paul Willging J., Cotton R. T., et al. (2002). Left ventricular hypertrophy and abnormal ventricular geometry in children and adolescents with obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 165, 1395–1399. 10.1164/rccm.210511810.1164/rccm.210511812016102Amoasii L., Hildyard J. C. W., Li H., Sanchez-Ortiz E., Mireault A., Caballero D., et al. (2018). Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science 362, 86–91. 10.1126/science.aau154910.1126/science.aau1549PMC620522830166439Amoasii L., Long C., Li H., Mireault A. A., Shelton J. M., Sanchez-Ortiz E., et al. (2017). Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy. Sci. Transl. Med. 9, eaan8081. 10.1126/scitranslmed.aan808110.1126/scitranslmed.aan8081PMC574940629187645Andrade F. H., Reid M. B., Allen D. G., Westerblad H. (1998). Effect of hydrogen peroxide and dithiothreitol on contractile function of single skeletal muscle fibres from the mouse. J. Physiol. 509 (2), 565–575. 10.1111/j.1469-7793.1998.565bn.x10.1111/j.1469-7793.1998.565bn.xPMC22309649575304Angelini C., Peterle E. (2012). Old and new therapeutic developments in steroid treatment in Duchenne muscular dystrophy. Acta Myol. 31, 9–15.PMC344080622655511Anzalone A. V., Koblan L. W., Liu D. R. (2020). Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat. Biotechnol. 38, 824–844. 10.1038/s41587-020-0561-910.1038/s41587-020-0561-932572269Anzalone A. V., Randolph P. B., Davis J. R., Sousa A. A., Koblan L. W., Levy J. M., et al. (2019). Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149–157. 10.1038/s41586-019-1711-410.1038/s41586-019-1711-4PMC690707431634902Arechavala V., Kinali M., Feng L., Brown S. C., Sewry C., Morgan J. E., et al. (2010). Immunohistological intensity measurements as a tool to assess sarcolemma-associated protein expression. Neuropathol. Appl. Neurobiol. 36, 265–274. 10.1111/j.1365-2990.2009.01056.x10.1111/j.1365-2990.2009.01056.x20002311Arechavala-Gomeza V., Graham I. R., Popplewell L. J., Adams A. M., Aartsma-Rus A., Kinali M., et al. (2007). Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Hum. Gene Ther. 18, 798–810. 10.1089/hum.2006.06110.1089/hum.2006.06117767400Arnett A. L. H., Konieczny P., Ramos J. N., Hall J., Odom G., Yablonka-Reuveni Z., et al. (2014). Adeno-associated viral vectors do not efficiently target muscle satellite cells. Mol. Therapy-Methods Clin. Dev. 1, 14038. 10.1038/mtm.2014.3810.1038/mtm.2014.38PMC428846425580445Attie K. M., Borgstein N. G., Yang Y., Condon C. H., Seehra J. A. S. S., Sherman M. L. (2013). A single ascending-dose study of muscle regulator ace-031 in healthy volunteers. 10.1002/mus.2353910.1002/mus.2353923169607Auld D. S., Thorne N., Maguire W. F., Inglese J. (2009). Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression. Proc. Natl. Acad. Sci. U. S. A. 106, 3585–3590. 10.1073/pnas.081334510610.1073/pnas.0813345106PMC263873819208811Bach J. R., Ishikawa Y., Kim H. (1997). Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy. Chest 112, 1024–1028. 10.1378/chest.112.4.102410.1378/chest.112.4.10249377912Ballas S. K., Files B., Luchtman-Jones L., Benjamin L., Swerdlow P., Hilliard L., et al. (2004). Safety of purified poloxamer 188 in sickle cell disease: phase I study of a non-ionic surfactant in the management of acute chest syndrome. Hemoglobin 28, 85–102. 10.1081/hem-12003591910.1081/hem-12003591915182051Banks G. B., Combs A. C., Chamberlain J. R., Chamberlain J. S. (2008). Molecular and cellular adaptations to chronic myotendinous strain injury in mdx mice expressing a truncated dystrophin. Hum. Mol. Genet. 17, 3975–3986. 10.1093/hmg/ddn30110.1093/hmg/ddn301PMC263858018799475Banks G. B., Gregorevic P., Allen J. M., Finn E. E., Chamberlain J. S. (2007). Functional capacity of dystrophins carrying deletions in the N-terminal actin-binding domain. Hum. Mol. Genet. 16, 2105–2113. 10.1093/hmg/ddm15810.1093/hmg/ddm15817588958Banks G. B., Judge L. M., Allen J. M., Chamberlain J. S. (2010). The polyproline site in hinge 2 influences the functional capacity of truncated dystrophins. PLoS Genet. 6, e1000958. 10.1371/journal.pgen.100095810.1371/journal.pgen.1000958PMC287392420502633Bansal D., Miyake K., Vogel S. S., Groh S., Chen C. C., Williamson R., et al. (2003). Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172. 10.1038/nature0157310.1038/nature0157312736685Barton-Davis E. R., Cordier L., Shoturma D. I., Leland S. E., Sweeney H. L. (1999). Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J. Clin. Investigation 104, 375–381. 10.1172/JCI786610.1172/JCI7866PMC48105010449429Bassi E., Falzarano S., Fabris M., Gualandi F., Merlini L., Vattemi G., et al. (2012). Persistent dystrophin protein restoration 90 days after a course of intraperitoneally administered naked 2′ OMePS AON and ZM2 NP-AON complexes in mdx mice. J. Biomed. Biotechnol. 2012, 897076. 10.1155/2012/89707610.1155/2012/897076PMC347106523091362Bates F. S., Fredrickson G. H. (1990). Block copolymer thermodynamics: Theory and experiment. Annu. Rev. Phys. Chem. 41, 525–557. 10.1146/annurev.pc.41.100190.00252110.1146/annurev.pc.41.100190.00252120462355Bedair H. S., Karthikeyan T., Quintero A., Li Y., Huard J. (2008). Angiotensin II receptor blockade administered after injury improves muscle regeneration and decreases fibrosis in normal skeletal muscle. Am. J. Sports Med. 36, 1548–1554. 10.1177/036354650831547010.1177/036354650831547018550776Benditt J. O., Boitano L. (2005). Respiratory support of individuals with Duchenne muscular dystrophy: Toward a standard of care. Phys. Med. Rehabil. Clin. N. Am. 16, 1125–1139. 10.1016/j.pmr.2005.08.01710.1016/j.pmr.2005.08.01716214065Bengtsson N. E., Hall J. K., Odom G. L., Phelps M. P., Andrus C. R., Hawkins R. D., et al. (2017). Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. Nat. Commun. 8, 14454–14510. 10.1038/ncomms1445410.1038/ncomms14454PMC531686128195574Beringer P., Winter M. E. (2011). “Aminoglycoside antibiotics,” in Basic clinical pharmacokinetics Fifth Edition, 134–181. 10.1002/9783527678679.dg0040310.1002/9783527678679.dg00403Bhattarai S., Li Q., Ding J., Liang F., Gusev E., Lapohos O., et al. (2022). TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy. Nat. Commun. 13, 879. 10.1038/s41467-022-28531-110.1038/s41467-022-28531-1PMC884742535169163Bidou L., Allamand V., Rousset J. P., Namy O. (2012). Sense from nonsense: Therapies for premature stop codon diseases. Trends Mol. Med. 18, 679–688. 10.1016/j.molmed.2012.09.00810.1016/j.molmed.2012.09.00823083810Birch S. M., Lawlor M. W., Conlon T. J., Guo L. J., Crudele J. M., Hawkins E. C., et al. (2023). Assessment of systemic AAV-microdystrophin gene therapy in the GRMD model of Duchenne muscular dystrophy. Sci. Transl. Med. 15, eabo1815. 10.1126/scitranslmed.abo181510.1126/scitranslmed.abo1815PMC1110774836599002Birnkrant D. J., Bushby K., Bann C. M., Apkon S. D., Blackwell A., Colvin M. K., et al. (2018). Diagnosis and management of duchenne muscular dystrophy, part 3: Primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Lancet Neurol. 17, 445–455. 10.1016/S1474-4422(18)30026-710.1016/S1474-4422(18)30026-7PMC590240829398641Bladen C. L., Salgado D., Monges S., Foncuberta M. E., Kekou K., Kosma K., et al. (2015). The TREAT‐NMD DMD global database: Analysis of more than 7,000 duchenne muscular dystrophy mutations. Hum. Mutat. 36, 395–402. 10.1002/humu.2275810.1002/humu.22758PMC440504225604253Boland B. J., Silbert P. L., Groover R. V., Wollan P. C., Silverstein M. D. (1996). Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophy. Pediatr. Neurol. 14, 7–12. 10.1016/0887-8994(95)00251-010.1016/0887-8994(95)00251-08652023Bordeira-Carriço R., Pêgo A. P., Santos M., Oliveira C. (2012). Cancer syndromes and therapy by stop-codon readthrough. Trends Mol. Med. 18, 667–678. 10.1016/j.molmed.2012.09.00410.1016/j.molmed.2012.09.00423044248Boutin S., Monteilhet V., Veron P., Leborgne C., Benveniste O., Montus M. F., et al. (2010). Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: Implications for gene therapy using AAV vectors. Hum. Gene Ther. 21, 704–712. 10.1089/hum.2009.18210.1089/hum.2009.18220095819Boyce F. M., Beggs A. H., Feener C., Kunkel L. M. (1991). Dystrophin is transcribed in brain from a distant upstream promoter. Proc. Natl. Acad. Sci. U. S. A. 88, 1276–1280. 10.1073/pnas.88.4.127610.1073/pnas.88.4.1276PMC510001996328Brashear S. E., Wohlgemuth R. P., Gonzalez G., Smith L. R. (2021). Passive stiffness of fibrotic skeletal muscle in mdx mice relates to collagen architecture. J. Physiol. 599, 943–962. 10.1113/JP28065610.1113/JP280656PMC992697433247944Briggs D., Morgan J. E. (2013). Recent progress in satellite cell/myoblast engraftment - relevance for therapy. FEBS J. 280, 4281–4293. 10.1111/febs.1227310.1111/febs.12273PMC379544023560812Briston T., Selwood D. L., Szabadkai G., Duchen M. R. (2019). Mitochondrial permeability transition: A molecular lesion with multiple drug targets. Trends Pharmacol. Sci. 40, 50–70. 10.1016/j.tips.2018.11.00410.1016/j.tips.2018.11.00430527591Buddhe S., Cripe L., Friedland-little J., Eghtesady P., Finder J., Hor K., et al. (2019)., 142. Cardiac, S72–S81. 10.1542/peds.2018-0333I Cardiac management of the patient with duchenne muscular dystrophy HHS Public Access10.1542/peds.2018-0333IPMC656685230275251Büning H., Schmidt M. (2015). Adeno-associated vector toxicity—To be or not to be? Mol. Ther. 23, 1673–1675. 10.1038/mt.2015.18210.1038/mt.2015.182PMC481794926606658Burkin D. J., Kaufman S. J. (1999). The α 7 β 1 integrin in muscle development and disease, 183–190.10199978Burkin D. J., Wallace G. Q., Milner D. J., Chaney E. J., Mulligan J. A., Kaufman S. J. (2005). Transgenic expression of {alpha}7{beta}1 integrin maintains muscle integrity, increases regenerative capacity, promotes hypertrophy, and reduces cardiomyopathy in dystrophic mice. Increases Regen. Capacity , Promot. Hypertrophy , Reduces Cardiomyopathy Dystrophic Mice 166, 253–263. 10.1016/s0002-9440(10)62249-310.1016/s0002-9440(10)62249-3PMC160228715632017Burkin D. J., Wallace G. Q., Nicol K. J., Kaufman D. J., Kaufman S. J. (2001). Enhanced expression of the alpha 7 beta 1 integrin reduces muscular dystrophy and restores viability in dystrophic mice Dystrophy Restores Viability Dystrophic Mice 152, 1207–1218. 10.1083/jcb.152.6.120710.1083/jcb.152.6.1207PMC219921311257121Burton E. A., Tinsley J. M., Holzfeind P. J., Rodrigues N. R., Davies K. E. (1999). A second promoter provides an alternative target for therapeutic up-regulation of utrophin in Duchenne muscular dystrophy, 96.PMC2418410570192Burzyn D., Kuswanto W., Kolodin D., Shadrach J. L., Cerletti M., Jang Y., et al. (2013). A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295. 10.1016/j.cell.2013.10.05410.1016/j.cell.2013.10.054PMC389474924315098Bushby K., Finkel R., Birnkrant D. J., Case L. E., Clemens P. R., Cripe L., et al. (2010). Diagnosis and management of duchenne muscular dystrophy, part 2: Implementation of multidisciplinary care. Lancet Neurol. 9, 177–189. 10.1016/S1474-4422(09)70272-810.1016/S1474-4422(09)70272-819945914Bushby K., Muntoni F., Urtizberea A., Hughes R., Griggs R. (2004). Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids 2-4 April 2004, Naarden, The Netherlands. Neuromuscul. Disord. 14, 526–534. 10.1016/j.nmd.2004.05.00610.1016/j.nmd.2004.05.00615336694Cai B., Spencer M. J., Nakamura G., Tseng-Ong L., Tidball J. G. (2000). Eosinophilia of dystrophin-deficient muscle is promoted by perforin-mediated cytotoxicity by T cell effectors. Am. J. Pathol. 156, 1789–1796. 10.1016/S0002-9440(10)65050-X10.1016/S0002-9440(10)65050-XPMC187690610793090Calcedo R., Vandenberghe L. H., Gao G., Lin J., Wilson J. M. (2009). Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 199, 381–390. 10.1086/59583010.1086/595830PMC1082692719133809Campbell C., Barohn R. J., Bertini E., Chabrol B., Comi P., Darras B. T., et al. (2020). Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy. J. Comp. Eff. Res. 9, 973–984. 10.2217/cer-2020-009510.2217/cer-2020-009532851872Campbell K. P., Kahl S. D. (1989). Association of dystrophin and an integral membrane glycoprotein. Nature 338, 259–262. 10.1038/338259a010.1038/338259a02493582Castiglioni A., Corna G., Rigamonti E., Basso V., Vezzoli M., Monno A., et al. (2015). FOXP3+ T cells recruited to sites of sterile skeletal muscle injury regulate the fate of satellite cells and guide effective tissue regeneration. PLoS One 10, e0128094. 10.1371/journal.pone.012809410.1371/journal.pone.0128094PMC445451326039259Cerletti M., Negri T., Cozzi F., Colpo R., Andreetta F., Croci D., et al. (2003). Dystrophic phenotype of canine X-linked muscular dystrophy is mitigated by adenovirus-mediated utrophin gene transfer. Gene Ther. 10, 750–757. 10.1038/sj.gt.330194110.1038/sj.gt.330194112704413Chamberlain J. R., Chamberlain J. S. (2017). Progress toward gene therapy for duchenne muscular dystrophy. Mol. Ther. 25, 1125–1131. 10.1016/j.ymthe.2017.02.01910.1016/j.ymthe.2017.02.019PMC541784428416280Chance B., Sies H., Boveris A. (1979). Hydroperoxide metabolism in mammalian organs. Physiol. Rev. 59, 527–605. 10.1152/physrev.1979.59.3.52710.1152/physrev.1979.59.3.52737532Chemello F., Bassel-duby R., Olson E. N. (2020). Correction of muscular dystrophies by CRISPR gene editing, 130.PMC725999832478678Chemello F., Chai A. C., Li H., Rodriguez-Caycedo C., Sanchez-Ortiz E., Atmanli A., et al. (2021). Precise correction of Duchenne muscular dystrophy exon deletion mutations by base and prime editing. Sci. Adv. 7, eabg4910. 10.1126/sciadv.abg491010.1126/sciadv.abg4910PMC808740433931459Chen G., Wei T., Yang H., Li G., Li H. (2022). CRISPR-based therapeutic gene editing for duchenne muscular dystrophy: Advances, challenges and perspectives. Cells 11, 2964. 10.3390/cells1119296410.3390/cells11192964PMC956408236230926Choi S., Ferrari G., Moyle L. A., Mackinlay K., Naouar N., Jalal S., et al. (2022). Assessing and enhancing migration of human myogenic progenitors using directed iPS cell differentiation and advanced tissue modelling. EMBO Mol. Med. 14, e14526. 10.15252/emmm.20211452610.15252/emmm.202114526PMC954973336161772Cisternas P., Vio C. P., Inestrosa N. C. (2014). Role of Wnt signaling in tissue fibrosis, lessons from skeletal muscle and kidney. Curr. Mol. Med. 14, 510–522. 10.2174/156652401466614041421034610.2174/156652401466614041421034624730522Clemens P. R., Rao V. K., Connolly A. M., Harper A. D., Mah J. K., Smith E. C., et al. (2020). Safety, tolerability, and efficacy of viltolarsen in boys with duchenne muscular dystrophy amenable to exon 53 skipping: A phase 2 randomized clinical trial. JAMA Neurol. 77, 982–991. 10.1001/jamaneurol.2020.126410.1001/jamaneurol.2020.1264PMC725150532453377Cohn R. D., Campbell K. P. (2000). Molecular basis of muscular dystrophies. Muscle Nerve 23, 1456–1471. 10.1002/1097-4598(200010)23:10<1456:AID-MUS2>3.0.CO;2-T10.1002/1097-4598(200010)23:10<1456:AID-MUS2>3.0.CO;2-T11003781Cole M. A., Rafael J. A., Taylor D. J., Lodi R., Davies K. E., Styles P. (2002). A quantitative study of bioenergetics in skeletal muscle lacking utrophin and dystrophin. Neuromuscul. Disord. 12, 247–257. 10.1016/s0960-8966(01)00278-410.1016/s0960-8966(01)00278-411801396 Collins J. M., Despa F., Lee R. C. (2007). Structural and functional recovery of electropermeabilized skeletal muscle in-vivo after treatment with surfactant poloxamer 188. Biochim. Biophys. Acta 1768, 1238–1246. 10.1016/j.bbamem.2007.01.012 10.1016/j.bbamem.2007.01.012PMC191940817382288Connolly A. M., Schierbecker J., Renna R., Florence J. (2002). High dose weekly oral prednisone improves strength in boys with Duchenne muscular dystrophy. Neuromuscul. Disord. 12, 917–925. 10.1016/S0960-8966(02)00180-310.1016/S0960-8966(02)00180-312467746Corrado K., Rafael J. A., Mills P. L., Cole N. M., Faulkner J. A., Wang K., et al. (1996). Transgenic mdx mice expressing dystrophin with a deletion in the actin-binding domain display a “‘mild becker’” phenotype. J. Cell Biol. 134, 873–884. 10.1083/jcb.134.4.87310.1083/jcb.134.4.873PMC21209628769413Cotton S., Voudouris N. J., Greenwood K. M. (2001). Intelligence and Duchenne muscular dystrophy: Full-scale, verbal, and performance intelligence quotients. Dev. Med. Child. Neurol. 43, 497–501. 10.1017/s001216220100091310.1017/s001216220100091311463183Crudele J. M., Chamberlain J. S. (2019). AAV-based gene therapies for the muscular dystrophies. Hum. Mol. Genet. 28, R102–R107. 10.1093/hmg/ddz12810.1093/hmg/ddz128PMC679699531238336Damsker J. M., Dillingham B. C., Rose M. C., Balsley M. A., Heier C. R., Watson A. M., et al. (2013). VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice. PLoS One 8, e63871–e63879. 10.1371/journal.pone.006387110.1371/journal.pone.0063871PMC364676923667681Deconinck A. E., Rafael J. A., Skinner J. A., Brown S. C., Potter A. C., Metzinger L., et al. (1997). Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 90, 717–727. 10.1016/S0092-8674(00)80532-210.1016/S0092-8674(00)80532-29288751Dellavalle A., Sampaolesi M., Tonlorenzi R., Tagliafico E., Sacchetti B., Perani L., et al. (2007). Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat. Cell Biol. 9, 255–267. 10.1038/ncb154210.1038/ncb154217293855Demina T., Grozdova I., Krylova O., Zhirnov A., Istratov V., Frey H., et al. (2005). Relationship between the structure of amphiphilic copolymers and their ability to disturb lipid bilayers. Biochemistry. 44, 4042–4054. 10.1021/bi048373q10.1021/bi048373q15751981Desguerre I., Christov C., Mayer M., Zeller R., Becane H. M., Bastuji-Garin S., et al. (2009). Clinical heterogeneity of Duchenne muscular dystrophy (DMD): Definition of sub-phenotypes and predictive criteria by long-term follow-up. PLoS One 4, e4347. 10.1371/journal.pone.000434710.1371/journal.pone.0004347PMC263304219194511Dominguez A. A., Lim W. A., Qi L. S. (2016). Beyond editing: Repurposing CRISPR-cas9 for precision genome regulation and interrogation. Nat. Rev. Mol. Cell Biol. 17, 5–15. 10.1038/nrm.2015.210.1038/nrm.2015.2PMC492251026670017Dong J. Y., Fan P. D., Frizzell R. A. (1996). Quantitative analysis of the packaging capacity of recombinant adeno-associated virus. Hum. Gene Ther. 7, 2101–2112. 10.1089/hum.1996.7.17-210110.1089/hum.1996.7.17-21018934224Doo K. H., Ryu H. W., Kim S. S., Lim B. C., Hwang H., Kim K. J., et al. (2012). A case of Becker muscular dystrophy with early manifestation of cardiomyopathy. Korean J. Pediatr. 55, 350–353. 10.3345/kjp.2012.55.9.35010.3345/kjp.2012.55.9.350PMC345457823049593Duan D. (2016a). Dystrophin gene replacement and gene repair therapy for duchenne muscular dystrophy in 2016: An interview. Hum. Gene Ther. Clin. Dev. 27, 9–18. 10.1089/humc.2016.00110.1089/humc.2016.001PMC485117627003751Duan D., Goemans N., Takeda S., Mercuri E., Aartsma-Rus A. (2021). Duchenne muscular dystrophy. Nat. Rev. Dis. Prim. 7, 13. 10.1038/s41572-021-00248-310.1038/s41572-021-00248-3PMC1055745533602943Duan D. (2018a). Micro-dystrophin gene therapy goes systemic in duchenne muscular dystrophy patients. Hum. Gene Ther. 29, 733–736. 10.1089/hum.2018.01210.1089/hum.2018.012PMC606619029463117Duan D. (2018b). Systemic AAV micro-dystrophin gene therapy for duchenne muscular dystrophy. Mol. Ther. 26, 2337–2356. 10.1016/j.ymthe.2018.07.01110.1016/j.ymthe.2018.07.011PMC617103730093306Duan D. (2016b). Systemic delivery of adeno-associated viral vectors. Curr. Opin. Virol. 21, 16–25. 10.1016/j.coviro.2016.07.00610.1016/j.coviro.2016.07.006PMC513807727459604 Duchene B. L., Cherif K., Iyombe-Engembe J. P., Guyon A., Rousseau J., Ouellet D. L., et al. (2018). CRISPR-induced deletion with SaCas9 restores dystrophin expression in dystrophic models in vitro and in vivo . Mol. Ther. 26, 2604–2616. 10.1016/j.ymthe.2018.08.010 10.1016/j.ymthe.2018.08.010PMC622477530195724Dupont J. B., Tournaire B., Georger C., Marolleau B., Jeanson-Leh L., Ledevin M., et al. (2015). Short-lived recombinant adeno-associated virus transgene expression in dystrophic muscle is associated with oxidative damage to transgene mRNA. Mol. Therapy-Methods Clin. Dev. 2, 15010. 10.1038/mtm.2015.1010.1038/mtm.2015.10PMC444500726029721Ebihara S., Guibinga G., Gilbert R., Nalbantoglu J., Massie B., Karpati G., et al. (2022). Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice, 133–144.11015608Echigoya Y., Nakamura A., Nagata T., Urasawa N., Lim K. R. Q., Trieu N., et al. (2017). Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. Proc. Natl. Acad. Sci. U. S. A. 114, 4213–4218. 10.1073/pnas.161320311410.1073/pnas.1613203114PMC540243728373570Emery A. E. H. (1993). Duchenne muscular dystrophy-Meryon’s disease. Neuromuscul. Disord. 3, 263–266. 10.1016/0960-8966(93)90018-F10.1016/0960-8966(93)90018-F8268722Emery A. E. H. (2002). “The muscular dystrophies,” in Lancet (Elsevier Limited; ), 687–695. 10.1016/S0140-6736(02)07815-710.1016/S0140-6736(02)07815-711879882England S. B., Nicholson L. V. B., Johnson M. A., Forrest S. M., Love D. R., Zubrzycka-Gaarn E. E., et al. (1990). Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 343, 180–182. 10.1038/343180a010.1038/343180a02404210Erkut E., Yokota T. (2022). CRISPR therapeutics for duchenne muscular dystrophy. Int. J. Mol. Sci. 23, 1832. 10.3390/ijms2303183210.3390/ijms23031832PMC883646935163754Ervasti J. M., Campbell K. P. (1993). A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J. Cell Biol. 122, 809–823. 10.1083/jcb.122.4.80910.1083/jcb.122.4.809PMC21195878349731Ervasti J. M., Campbell K. P. (1991). Membrane organization of the dystrophin-glycoprotein complex. Cell 66, 1121–1131. 10.1016/0092-8674(91)90035-W10.1016/0092-8674(91)90035-W1913804 Ervasti J. M. (2013). “Structure and function of the dystrophin-glycoprotein complex,” in Madame curie bioscience database. [Internet] (Landes Bioscience).Eser G., Topaloğlu H. (2022). Current outline of exon skipping trials in duchenne muscular dystrophy. Genes (Basel) 13, 1241. 10.3390/genes1307124110.3390/genes13071241PMC932032235886024Evans N. P., Misyak S. A., Robertson J. L., Bassaganya-Riera J., Grange R. W. (2009). Dysregulated intracellular signaling and inflammatory gene expression during initial disease onset in duchenne muscular dystrophy. Am. J. Phys. Med. Rehabil. 88, 502–522. 10.1097/PHM.0b013e3181a5a24f10.1097/PHM.0b013e3181a5a24f19454857Ferlini A., Sabatelli P., Fabris M., Bassi E., Falzarano S., Vattemi G., et al. (2010). Dystrophin restoration in skeletal, heart and skin arrector pili smooth muscle of mdx mice by ZM2 NP-AON complexes. Gene Ther. 17, 432–438. 10.1038/gt.2009.14510.1038/gt.2009.14519907501Flanigan K. M. (2014). Duchenne and becker muscular dystrophies. Neurol. Clin. 32, 671–688. 10.1016/j.ncl.2014.05.00210.1016/j.ncl.2014.05.00225037084Foster H., Sharp P. S., Athanasopoulos T., Trollet C., Graham I. R., Foster K., et al. (2008). Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer. Mol. Ther. 16, 1825–1832. 10.1038/mt.2008.18610.1038/mt.2008.18618766174Frank D. E., Schnell F. J., Akana C., El-husayni S. H. (2020). Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. 10.1212/WNL.000000000000923310.1212/WNL.0000000000009233PMC735729732139505Fridovich I. (2004). Mitochondria: Are they the seat of senescence? Aging Cell 3, 13–16. 10.1046/j.1474-9728.2003.00075.x10.1046/j.1474-9728.2003.00075.x14965350Gadgil A., Raczyńska K. D. (2021). U7 snRNA: A tool for gene therapy. J. Gene Med. 23, 1–15. 10.1002/jgm.332110.1002/jgm.3321PMC824393533590603 Gailly P., De Backer F., Van Schoor M., Gillis J. M. (2007). In situ measurements of calpain activity in isolated muscle fibres from normal and dystrophin-lacking mdx mice. J. Physiology 582, 1261–1275. 10.1113/jphysiol.2007.132191 10.1113/jphysiol.2007.132191PMC207523617510188Gallardo F. S., Cordova-Casanova A., Brandan E. (2021). The linkage between inflammation and fibrosis in muscular dystrophies: The axis autotaxin-lysophosphatidic acid as a new therapeutic target? J. Cell Commun. Signal 15, 317–334. 10.1007/s12079-021-00610-w10.1007/s12079-021-00610-wPMC822248333689121 Gao G., Vandenberghe L. H., Alvira M. R., Lu Y., Calcedo R., Zhou X., et al. (2004). Clades of Adeno-associated viruses are widely disseminated in human tissues. J. Virol. 78, 6381–6388. 10.1128/JVI.78.12.6381-6388.2004 10.1128/JVI.78.12.6381-6388.2004PMC41654215163731Gao Q., McNally E. (2015). The dystrophin complex: Structure, function, and implications for therapy. Compr. Physiol. 5, 1223–1239. 10.1002/cphy.c14004810.1002/cphy.c140048PMC476726026140716Gapinske M., Luu A., Winter J., Woods W. S., Kostan K. A., Shiva N. (2018). CRISPR-SKIP: Programmable gene splicing with single base editors, 1–11.PMC609278130107853Garcia-Castaneda M., Michelucci A., Zhao N., Malik S., Dirksen R. T. (2022). Postdevelopmental knockout of Orai1 improves muscle pathology in a mouse model of Duchenne muscular dystrophy. J. Gen. Physiol. 154, e202213081. 10.1085/jgp.20221308110.1085/jgp.202213081PMC936587435939054Gardner K. L., Kearney J. A., Edwards J. D., Rafael-Fortney J. A. (2006). Restoration of all dystrophin protein interactions by functional domains in trans does not rescue dystrophy. Gene Ther. 13, 744–751. 10.1038/sj.gt.330268610.1038/sj.gt.330268616307000Gaudelli N. M., Komor A. C., Rees H. A., Packer M. S., Badran A. H., Bryson D. I., et al. (2017). Programmable base editing of A • T to G • C in genomic DNA without DNA cleavage. Nat. Publ. Group 551, 464–471. 10.1038/nature2464410.1038/nature24644PMC572655529160308Gawlik K. I., Oliveira B. M., Durbeej M. (2011). Transgenic expression of laminin ␣ 1 chain does not prevent muscle disease in the mdx mouse model for duchenne muscular dystrophy. AJPA 178, 1728–1737. 10.1016/j.ajpath.2010.12.03010.1016/j.ajpath.2010.12.030PMC307843021435454Gehlert S., Jacko D. (2019). The role of the immune system in response to muscle damage. Dtsch. Z Sportmed 70, 242–249. 10.5960/dzsm.2019.39010.5960/dzsm.2019.390Giordano C., Mojumdar K., Liang F., Lemaire C., Li T., Richardson J., et al. (2015). Toll-like receptor 4 ablation in mdx mice reveals innate immunity as a therapeutic target in Duchenne muscular dystrophy. Hum. Mol. Genet. 24, 2147–2162. 10.1093/hmg/ddu73510.1093/hmg/ddu735PMC438006525552658Glancy B., Hartnell L. M., Malide D., Yu Z. X., Combs C. A., Connelly P. S., et al. (2015). Mitochondrial reticulum for cellular energy distribution in muscle. Nature 523, 617–620. 10.1038/nature1461410.1038/nature14614PMC698872826223627Godin R., Daussin F., Matecki S., Li T., Petrof B. J., Burelle Y. (2012). Peroxisome proliferator-activated receptor gamma coactivator1-gene alpha transfer restores mitochondrial biomass and improves mitochondrial calcium handling in post-necrotic mdx mouse skeletal muscle. J. Physiol. 590, 5487–5502. 10.1113/jphysiol.2012.24039010.1113/jphysiol.2012.240390PMC351583322907054Goldmann T., Overlack N., Möller F., Belakhov V., van Wyk M., Baasov T., et al. (2012). A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation. EMBO Mol. Med. 4, 1186–1199. 10.1002/emmm.20120143810.1002/emmm.201201438PMC349487523027640Gordon A. M., Homsher E., Regnier M. (2000). Regulation of contraction in striated muscle. Physiol. Rev. 80, 853–924. 10.1152/physrev.2000.80.2.85310.1152/physrev.2000.80.2.85310747208Goyenvalle A., Seto J. T., Davies K. E., Chamberlain J. (2011). Therapeutic approaches to muscular dystrophy. Hum. Mol. Genet. 20, R69–R78. 10.1093/hmg/ddr10510.1093/hmg/ddr105PMC309506221436158Goyenvalle A., Wright J., Babbs A., Wilkins V., Garcia L., Davies K. E. (2012). Engineering multiple U7snRNA constructs to induce single and multiexon-skipping for Duchenne muscular dystrophy. Mol. Ther. 20, 1212–1221. 10.1038/mt.2012.2610.1038/mt.2012.26PMC336940622354379Gregorevic P., Allen J. M., Minami E., Blankinship M. J., Haraguchi M., Inn E., et al. (2006). rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat. Med. 12, 787–789. 10.1038/nm143910.1038/nm1439PMC424488316819550Gregorevic P., Blankinship M. J., Allen J. M., Crawford R. W., Meuse L., Miller D. G., et al. (2004). Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat. Med. 10, 828–834. 10.1038/nm108510.1038/nm1085PMC136504615273747Grobet L., Pirottin D., Poncelet D., Royo L. J., Christians E., Desmecht D., et al. (2003). Modulating skeletal muscle mass by postnatal, muscle-specific inactivation of the myostatin gene. Muscle-Specific Inact. Myostatin Gene 238, 227–238. 10.1002/gene.1018810.1002/gene.1018812717734Grounds M. D., Terrill J. R., Al-Mshhdani B. A., Duong M. N., Radley-Crabb H. G., Arthur P. G. (2020). Biomarkers for Duchenne muscular dystrophy: Myonecrosis, inflammation and oxidative stress. DMM Dis. Models Mech. 13, dmm043638–12. 10.1242/DMM.04363810.1242/DMM.043638PMC706366932224496Guiraud S., Aartsma-Rus A., Vieira N. M., Davies K. E., Van Ommen G. J. B., Kunkel L. M. (2015). The pathogenesis and therapy of muscular dystrophies. Annu. Rev. Genomics Hum. Genet. 16, 281–308. 10.1146/annurev-genom-090314-02500310.1146/annurev-genom-090314-02500326048046Guo C., Willem M., Werner A., Raivich G., Emerson M., Neyses L., et al. (2006). Absence of alpha 7 integrin in dystrophin-deficient mice causes a myopathy similar to Duchenne muscular dystrophy. Hum. Mol. Genet. 15, 989–998. 10.1093/hmg/ddl01810.1093/hmg/ddl01816476707Gurpur P. B., Liu J., Burkin D. J., Kaufman S. J. (2009). Valproic acid activates the PI3K/Akt/mTOR pathway in muscle and ameliorates pathology in a mouse model of Duchenne muscular dystrophy. Dystrophy 174, 999–1008. 10.2353/ajpath.2009.08053710.2353/ajpath.2009.080537PMC266575919179609Gushchina L. V., Frair E. C., Rohan N., Bradley A. J., Simmons T. R., Chavan H. D., et al. (2021). Lack of toxicity in nonhuman primates receiving clinically relevant doses of an AAV9.U7snRNA vector designed to induce DMD exon 2 skipping. Hum. Gene Ther. 32, 882–894. 10.1089/hum.2020.28610.1089/hum.2020.286PMC1011246133406986Hahn D., Kumar R. A., Ryan T. E., Ferreira L. F. (2019). Mitochondrial respiration and H2O2 emission in saponin-permeabilized murine diaphragm fibers: Optimization of fiber separation and comparison to limb muscle. Am. J. Physiol. Cell Physiol. 317, C665–C673. 10.1152/ajpcell.00184.201910.1152/ajpcell.00184.2019PMC685100131314583Hakim C. H., Wasala N. B., Pan X., Kodippili K., Yue Y., Zhang K., et al. (2017). A five-repeat micro-dystrophin gene ameliorated dystrophic phenotype in the severe DBA/2J-mdx model of duchenne muscular dystrophy. Mol. Ther. Methods Clin. Dev. 6, 216–230. 10.1016/j.omtm.2017.06.00610.1016/j.omtm.2017.06.006PMC559650328932757Hannig J., Yu J., Beckett M., Weichselbaum R., Lee R. C. (1999). Poloxamine 1107 sealing of radiopermeabilized erythrocyte membranes. Int. J. Radiat. Biol. 75, 379–385. 10.1080/09553009914055510.1080/09553009914055510203188Hanson B., Wood M. J. A., Roberts T. C. (2021). Molecular correction of Duchenne muscular dystrophy by splice modulation and gene editing. RNA Biol. 18, 1048–1062. 10.1080/15476286.2021.187416110.1080/15476286.2021.1874161PMC821618733472516Happi Mbakam C., Lamothe G., Tremblay G., Tremblay J. P. (2022a). CRISPR-Cas9 gene therapy for duchenne muscular dystrophy. Neurotherapeutics 19, 931–941. 10.1007/s13311-022-01197-910.1007/s13311-022-01197-9PMC929408635165856Happi Mbakam C., Rousseau J., Tremblay G., Yameogo P., Tremblay J. P. (2022b). Prime editing permits the introduction of specific mutations in the gene responsible for duchenne muscular dystrophy. Int. J. Mol. Sci. 23, 6160. 10.3390/ijms2311616010.3390/ijms23116160PMC918122435682838Harper S. Q., Hauser M. A., DelloRusso C., Duan D., Crawford R. W., Phelps S. F., et al. (2002). Modular flexibility of dystrophin: Implications for gene therapy of duchenne muscular dystrophy. Nat. Med. 8, 253–261. 10.1038/nm0302-25310.1038/nm0302-25311875496 Heemskerk H. A., de Winter C. L., de Kimpe S. J., van Kuik-Romeijn P., Heuvelmans N., Platenburg G. J., et al. (2009). In vivo comparison of 2’-O-methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping. J. Gene Med. 11, 257–266. 10.1002/jgm.1288 10.1002/jgm.128819140108Heemskerk H., de Winter C., van Kuik P., Heuvelmans N., Sabatelli P., Rimessi P., et al. (2010). Preclinical PK and PD studies on 2’-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model. Mol. Ther. 18, 1210–1217. 10.1038/mt.2010.7210.1038/mt.2010.72PMC288973320407428Heier C. R., Damsker J. M., Yu Q., Dillingham B. C., Huynh T., Van der Meulen J. H., et al. (2013). VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol. Med. 5, 1569–1585. 10.1002/emmm.20130262110.1002/emmm.201302621PMC379958024014378Heier C. R., Yu Q., Fiorillo A. A., Tully C. B., Tucker A., Mazala D. A., et al. (2019). Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy. Life Sci. Alliance 2, e201800186. 10.26508/LSA.20180018610.26508/LSA.201800186PMC637119630745312Heller K. N., Montgomery C. L., Janssen P. M., Clark K. R., Mendell J. R., Rodino-Klapac L. R. (2013). AAV-mediated overexpression of human α7 integrin leads to histological and functional improvement in dystrophic mice. Mol. Ther. 21, 520–525. 10.1038/mt.2012.28110.1038/mt.2012.281PMC358916723319059Hendriksen J. G. M., Vles J. S. H. (2006). Are males with duchenne muscular dystrophy at risk for reading disabilities? Pediatr. Neurol. 34, 296–300. 10.1016/j.pediatrneurol.2005.08.02910.1016/j.pediatrneurol.2005.08.02916638505Hendriksen J. G. M., Vles J. S. H. (2008). Neuropsychiatric disorders in males with duchenne muscular dystrophy: Frequency rate of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, and obsessive-compulsive disorder. J. Child. Neurol. 23, 477–481. 10.1177/088307380730977510.1177/088307380730977518354150Henriques-Pons A., Yu Q., Rayavarapu S., Cohen T. v., Ampong B., Cha H. J., et al. (2014). Role of toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle. Hum. Mol. Genet. 23, 2604–2617. 10.1093/hmg/ddt65610.1093/hmg/ddt656PMC399016124368419Hodges B. L., Hayashi Y. K., Nonaka I., Wang W., Arahata K., Kaufman S. J. (1997). Altered expression of the alpha7beta1 integrin in human and murine muscular dystrophies. J. Cell Sci. 2881, 2873–2881. 10.1242/jcs.110.22.287310.1242/jcs.110.22.28739427295Hoffman E. P., Bronson A., Levin A. A., Takeda S., Yokota T., Baudy A. R., et al. (2011). Restoring dystrophin expression in duchenne muscular dystrophy muscle progress in exon skipping and stop codon read through. Am. J. Pathology 179, 12–22. 10.1016/j.ajpath.2011.03.05010.1016/j.ajpath.2011.03.050PMC312480421703390Hoffman E. P., Brown R. H., Kunkel L. M. (1987). Dystrophin: The protein product of the duchenne muscular dystrophy locus. Cell 51, 919–928. 10.1016/0092-8674(87)90579-410.1016/0092-8674(87)90579-43319190Hogrel J.-Y., Zagnoli F., Canal A., Fraysse B., Bouchard J.-P., Skuk D., et al. (2013). Assessment of a symptomatic Duchenne muscular dystrophy carrier 20years after myoblast transplantation from her asymptomatic identical twin sister. Neuromuscul. Disord. 23, 575–579. 10.1016/j.nmd.2013.04.00710.1016/j.nmd.2013.04.00723731976Hopf F. W., Turner P. R., Denetclaw W. F., Reddy P., Steinhardt R. A. (1996). A critical evaluation of resting intracellular free calcium regulation in dystrophic mdx muscle. Am. J. Physiol. - Cell Physiol. 271, C1325–C1339. 10.1152/ajpcell.1996.271.4.c132510.1152/ajpcell.1996.271.4.c13258897840 Houang E. M., Haman K. J., Filareto A., Perlingeiro R. C., Bates F. S., Lowe D. A., et al. (2015). Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo . Mol. Ther. Methods Clin. Dev. 2, 15042. 10.1038/mtm.2015.42 10.1038/mtm.2015.42PMC464151126623440Houang E. M., Haman K. J., Kim M., Zhang W., Lowe D. A., Sham Y. Y., et al. (2017). Chemical end group modified diblock copolymers elucidate anchor and chain mechanism of membrane stabilization. Mol. Pharm. 14, 2333–2339. 10.1021/acs.molpharmaceut.7b0019710.1021/acs.molpharmaceut.7b00197PMC564805928538101Houang E. M., Sham Y. Y., Bates F. S., Metzger J. M. (2018). Muscle membrane integrity in duchenne muscular dystrophy: Recent advances in copolymer-based muscle membrane stabilizers. Skelet. Muscle 8, 31. 10.1186/s13395-018-0177-710.1186/s13395-018-0177-7PMC618050230305165Huang T. P., Newby G. A., Liu D. R. (2021). Precision genome editing using cytosine and adenine base editors in mammalian cells. Nat. Protoc. 16, 1089–1128. 10.1038/s41596-020-00450-910.1038/s41596-020-00450-933462442Hughes M. C., Ramos S. V., Turnbull P. C., Edgett B. A., Huber J. S., Polidovitch N., et al. (2020). Impairments in left ventricular mitochondrial bioenergetics precede overt cardiac dysfunction and remodelling in Duchenne muscular dystrophy. J. Physiol. 598, 1377–1392. 10.1113/JP27730610.1113/JP27730630674086Hughes M. C., Ramos S. V., Turnbull P. C., Rebalka I. A., Cao A., Monaco C. M. F., et al. (2019). Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H2 O2 emission during impaired oxidative phosphorylation. J. Cachexia Sarcopenia Muscle 10, 643–661. 10.1002/jcsm.1240510.1002/jcsm.12405PMC659640330938481Hunter R. L., Luo A. Z., Zhang R., Kozar R. A., Moore F. A. (2010). Poloxamer 188 inhibition of ischemia/reperfusion injury: Evidence for a novel anti-adhesive mechanism. Ann. Clin. Lab. Sci. 40, 115–125.20421622Hurst S., Hoek J., Sheu S. S. (2017). Mitochondrial Ca2+ and regulation of the permeability transition pore. J. Bioenerg. Biomembr. 49, 27–47. 10.1007/s10863-016-9672-x10.1007/s10863-016-9672-xPMC539327327497945Hynes R. (1992). Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 69 (1), 11–25. 10.1016/0092-8674(92)90115-s10.1016/0092-8674(92)90115-s1555235Ishikawa-Sakurai M., Yoshida M., Imamura M., Davies K. E., Ozawa E. (2004). ZZ domain is essentially required for the physiological binding of dystrophin and utrophin to β-dystroglycan. Hum. Mol. Genet. 13, 693–702. 10.1093/hmg/ddh08710.1093/hmg/ddh08714962982Iyombe-Engembe J.-P., Ouellet D. L., Barbeau X., Rousseau J., Chapdelaine P., Lagüe P., et al. (2016). Efficient restoration of the dystrophin gene reading frame and protein structure in DMD myoblasts using the CinDel method. Mol. Therapy-Nucleic Acids 5, e283. 10.1038/mtna.2015.5810.1038/mtna.2015.58PMC501255426812655Jearawiriyapaisarn N., Moulton H. M., Buckley B., Roberts J., Sazani P., Fucharoen S., et al. (2008). Sustained dystrophin expression induced by peptide-conjugated morpholino oligomers in the muscles of mdx mice. Mol. Ther. 16, 1624–1629. 10.1038/mt.2008.12010.1038/mt.2008.120PMC267167618545222Jearawiriyapaisarn N., Moulton H. M., Sazani P., Kole R., Willis M. S. (2010). Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers. Cardiovasc Res. 85, 444–453. 10.1093/cvr/cvp33510.1093/cvr/cvp335PMC280220519815563Jinek M., Chylinski K., Fonfara I., Hauer M., Doudna J. A., Charpentier E. (2012). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821. 10.1126/science.122582910.1126/science.1225829PMC628614822745249 Jørgensen L. H., Larochelle N., Orlopp K., Dunant P., Dudley R. W. R., Stucka R., et al. (2009). Efficient and fast functional screening of microdystrophin constructs in vivo and in vitro for therapy of duchenne muscular dystrophy. Hum. Gene Ther. 20, 641–650. 10.1089/hum.2008.162 10.1089/hum.2008.16219239382Jung C., Martins A. S., Niggli E., Shirokova N. (2008). Dystrophic cardiomyopathy: Amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways. Cardiovasc Res. 77, 766–773. 10.1093/cvr/cvm08910.1093/cvr/cvm08918056762Jung D., Yang B., Meyer J., Chamberlain J. S., Campbell K. P. (1995). Identification and characterization of the dystrophin anchoring site on beta-dystroglycan. J. Biol. Chem. 270, 27305–27310. 10.1074/jbc.270.45.2730510.1074/jbc.270.45.273057592992Jungbluth H., Treves S., Zorzato F., Sarkozy A., Ochala J., Sewry C., et al. (2018). Congenital myopathies: Disorders of excitation-contraction coupling and muscle contraction. Nat. Rev. Neurol. 14, 151–167. 10.1038/nrneurol.2017.19110.1038/nrneurol.2017.19129391587Kamdar F., Garry D. J. (2016). Dystrophin-deficient cardiomyopathy. J. Am. Coll. Cardiol. 67, 2533–2546. 10.1016/j.jacc.2016.02.08110.1016/j.jacc.2016.02.08127230049Kang C., Badr M. A., Kyrychenko V., Eskelinen E. L., Shirokova N. (2018). Deficit in PINK1/PARKIN-mediated mitochondrial autophagy at late stages of dystrophic cardiomyopathy. Cardiovasc Res. 114, 90–102. 10.1093/cvr/cvx20110.1093/cvr/cvx201PMC585252429036556Kawecka K., Theodoulides M., Hasoglu Y., Jarmin S., Kymalainen H., Le-Heron A., et al. (2015). Adeno-associated virus (AAV) mediated dystrophin gene transfer studies and exon skipping strategies for duchenne muscular dystrophy (DMD). Curr. Gene Ther. 15, 395–415. 10.2174/156652321566615071012383010.2174/156652321566615071012383026159373Kerem E., Konstan M. W., De Boeck K., Accurso F. J., Sermet-Gaudelus I., Wilschanski M., et al. (2014). Ataluren for the treatment of nonsense-mutation cystic fibrosis: A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir. Med. 2, 539–547. 10.1016/S2213-2600(14)70100-610.1016/S2213-2600(14)70100-6PMC415431124836205Kessler P. D., Podsakoff G. M., Chen X., McQuiston S. A., Colosi P. C., Matelis L. A., et al. (1996). Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc. Natl. Acad. Sci. U. S. A. 93, 14082–14087. 10.1073/pnas.93.24.1408210.1073/pnas.93.24.14082PMC194988943064Khairallah R. J., Shi G., Sbrana F., Prosser B. L., Borroto C., Mazaitis M. J., et al. (2012). Microtubules underlie dysfunction in duchenne muscular dystrophy. Sci. Signal 5, ra56. 10.1126/scisignal.200282910.1126/scisignal.2002829PMC383566022871609Kharraz Y., Guerra J., Pessina P., Serrano A. L., Munoz-Canoves P. (2014). Understanding the process of fibrosis in Duchenne muscular dystrophy. Biomed. Res. Int. 2014, 965631. 10.1155/2014/96563110.1155/2014/965631PMC402441724877152Kim J. H., Kwak H. B., Thompson L. V., Lawler J. M. (2013). Contribution of oxidative stress to pathology in diaphragm and limb muscles with Duchenne muscular dystrophy. J. Muscle Res. Cell Motil. 34, 1–13. 10.1007/s10974-012-9330-910.1007/s10974-012-9330-923104273 Kim M., Haman K. J., Houang E. M., Zhang W., Yannopoulos D., Metzger J. M., et al. (2017). PEO-PPO diblock copolymers protect myoblasts from hypo-osmotic stress in vitro dependent on copolymer size, composition, and architecture. Biomacromolecules 18, 2090–2101. 10.1021/acs.biomac.7b00419 10.1021/acs.biomac.7b00419PMC564025628535058Kim M. J., Bible K. L., Regnier M., Adams M. E., Froehner S. C., Whitehead N. P. (2019). Simvastatin provides long-term improvement of left ventricular function and prevents cardiac fibrosis in muscular dystrophy. Physiol. Rep. 7, e14018. 10.14814/phy2.1401810.14814/phy2.14018PMC643417130912308Kim S., Kim D., Cho S. W., Kim J., Kim J. S. (2014). Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins. Genome Res. 24, 1012–1019. 10.1101/gr.171322.11310.1101/gr.171322.113PMC403284724696461Kim T. ‐W., Wu K., Black I. B. (1995). Deficiency of brain synaptic dystrophin in human duchenne muscular dystrophy. Ann. Neurol. 38, 446–449. 10.1002/ana.41038031510.1002/ana.4103803157668831Klingler W., Jurkat-Rott K., Lehmann-Horn F., Schleip R. (2012). The role of fibrosis in Duchenne muscular dystrophy. Acta Myol. 31, 184–195.PMC363180223620650Knott G. J., Doudna J. A. (2018). CRISPR-Cas guides the future of genetic engineering. Science 361, 866–869. 10.1126/science.aat501110.1126/science.aat5011PMC645591330166482Koenig M., Kunkel L. M. (1990). Detailed analysis of the repeat domain of dystrophin reveals four potential hinge segments that may confer flexibility. J. Biol. Chem. 265, 4560–4566. 10.1016/s0021-9258(19)39599-710.1016/s0021-9258(19)39599-72407739Koenig M., Monaco A. P., Kunkel L. M. (1988). The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 53, 219–228. 10.1016/0092-8674(88)90383-210.1016/0092-8674(88)90383-23282674Komaki H., Takeshima Y., Matsumura T., Ozasa S., Funato M., Takeshita E., et al. (2020). Viltolarsen in Japanese duchenne muscular dystrophy patients: A phase 1/2 study. Ann. Clin. Transl. Neurol. 7, 2393–2408. 10.1002/acn3.5123510.1002/acn3.51235PMC773224033285037Komor A. C., Kim Y. B., Packer M. S., Zuris J. A., Liu D. R. (2016). Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424. 10.1038/nature1794610.1038/nature17946PMC487337127096365Koo T., Malerba A., Athanasopoulos T., Trollet C., Boldrin L., Ferry A., et al. (2011). Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of α1-syntrophin and α-dystrobrevin in skeletal muscles of mdx mice. Hum. Gene Ther. 22, 1379–1388. 10.1089/hum.2011.02010.1089/hum.2011.020PMC322504521453126Kotterman M. A., Schaffer D. V. (2014). Engineering adeno-associated viruses for clinical gene therapy. Nat. Rev. Genet. 15, 445–451. 10.1038/nrg374210.1038/nrg3742PMC439364924840552Krag T. O. B., Bogdanovich S., Jensen C. J., Fischer M. D., Hansen-schwartz J., Javazon E. H., et al. (2004). Heregulin ameliorates the dystrophic phenotype in mdx mice. Proc. Natl. Acad. Sci. U. S. A. 101, 13856–13860. 10.1073/pnas.040597210110.1073/pnas.0405972101PMC51876415365169Kuzmin D. A., Shutova M. V., Johnston N. R., Smith O. P., Johnstone E. C., Kukushkin Y. S., et al. (2021). The clinical landscape for AAV gene therapies. Nat. Rev. Drug Discov. 20, 173–174. 10.1038/d41573-021-00017-710.1038/d41573-021-00017-733495615Kyrychenko V., Kyrychenko S., Tiburcy M., Shelton J. M., Long C., Schneider J. W., et al. (2017). Functional correction of dystrophin actin binding domain mutations by genome editing. JCI Insight 2, e95918. 10.1172/jci.insight.9591810.1172/jci.insight.95918PMC562191328931764Kyrychenko V., Poláková E., Janíček R., Shirokova N. (2015). Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy. Cell Calcium 58, 186–195. 10.1016/j.ceca.2015.04.00610.1016/j.ceca.2015.04.006PMC450187625975620Lacourpaille L., Gross R., Hug F., Guevel A., Pereon Y., Magot A., et al. (2017). Effects of duchenne muscular dystrophy on muscle stiffness and response to electrically-induced muscle contraction: A 12-month follow-up. Neuromuscul. Disord. 27, 214–220. 10.1016/j.nmd.2017.01.00110.1016/j.nmd.2017.01.00128161094Lacourpaille L., Hug F., Guevel A., Pereon Y., Magot A., Hogrel J. Y., et al. (2015). Non-invasive assessment of muscle stiffness in patients with Duchenne muscular dystrophy. Muscle Nerve 51, 284–286. 10.1002/mus.2444510.1002/mus.2444525187068Lai Y., Thomas G. D., Yue Y., Yang H. T., Li D., Long C., et al. (2009). Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J. Clin. Invest. 119, 624–635. 10.1172/JCI3661210.1172/JCI36612PMC264869219229108 Lau C.-H., Suh Y. (2017). In vivo genome editing in animals using AAV-CRISPR system: Applications to translational research of human disease. F1000Res 6, 2153. 10.12688/f1000research.11243.1 10.12688/f1000research.11243.1PMC574912529333255Le Guiner C., Servais L., Montus M., Larcher T., Fraysse B., Moullec S., et al. (2017). Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Nat. Commun. 8, 16105–16115. 10.1038/ncomms1610510.1038/ncomms16105PMC553748628742067 Lee K., Conboy M., Park H. M., Jiang F., Kim H. J., Dewitt M. A., et al. (2017). Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair. Nat. Biomed. Eng. 1, 889–901. 10.1038/s41551-017-0137-2 10.1038/s41551-017-0137-2PMC596882929805845Lee R. C., Hannig J., Matthews K. L., Myerov A., Chen C. T. (1999). Pharmaceutical therapies for sealing of permeabilized cell membranes in electrical injuries. Ann. N. Y. Acad. Sci. 888, 266–273. 10.1111/j.1749-6632.1999.tb07961.x10.1111/j.1749-6632.1999.tb07961.x10842638 Lee R. C., River L. P., Pan F. S., Ji L., Wollmann R. L. (1992). Surfactant-induced sealing of electropermeabilized skeletal muscle membranes in vivo . Proc. Natl. Acad. Sci. U. S. A. 89, 4524–4528. 10.1073/pnas.89.10.4524 10.1073/pnas.89.10.4524PMC491151584787Lee S. J. (2004). Regulation of muscle mass by myostatin. Annu. Rev. Cell Dev. Biol. 20, 61–86. 10.1146/annurev.cellbio.20.012103.13583610.1146/annurev.cellbio.20.012103.13583615473835Lee T. H., Eun L. Y., Choi J. Y., Kwon H. E., Lee Y. M., Kim H. D., et al. (2014). Myocardial atrophy in children with mitochondrial disease and Duchenne muscular dystrophy. Korean J. Pediatr. 57, 232–239. 10.3345/kjp.2014.57.5.23210.3345/kjp.2014.57.5.232PMC410268625045366Levi O., Genin O., Angelini C., Halevy O., Pines M. (2015). Inhibition of muscle fibrosis results in increases in both utrophin levels and the number of revertant myofibers in Duchenne muscular dystrophy. Oncotarget 6, 23249–23260. 10.18632/oncotarget.402110.18632/oncotarget.4021PMC469511526015394Li H. L., Fujimoto N., Sasakawa N., Shirai S., Ohkame T., Sakuma T., et al. (2015). Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Rep. 4, 143–154. 10.1016/j.stemcr.2014.10.01310.1016/j.stemcr.2014.10.013PMC429788825434822Li J., Cao J., Li M., Yu Y., Yang Y., Xiao X., et al. (2011). Collagen triple helix repeat containing-1 inhibits transforming growth factor-b1-induced collagen type I expression in keloid. Br. J. Dermatol 164, 1030–1036. 10.1111/j.1365-2133.2011.10215.x10.1111/j.1365-2133.2011.10215.x21667528Li Z. B., Kollias H. D., Wagner K. R. (2008). Myostatin directly regulates skeletal muscle fibrosis. J. Biol. Chem. 283, 19371–19378. 10.1074/jbc.M80258520010.1074/jbc.M802585200PMC244365518453534Lieber R. L., Ward S. R. (2013). Cellular mechanisms of tissue fibrosis. 4. Structural and functional consequences of skeletal muscle fibrosis. Am. J. Physiol. Cell Physiol. 305, C241–C252. 10.1152/ajpcell.00173.201310.1152/ajpcell.00173.2013PMC374284523761627Long C., Amoasii L., Mireault A. A., McAnally J. R., Li H., Sanchez-Ortiz E., et al. (2016). Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351, 400–403. 10.1126/science.aad572510.1126/science.aad5725PMC476062826721683Long C., Li H., Tiburcy M., Rodriguez-Caycedo C., Kyrychenko V., Zhou H., et al. (2018). Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing. Sci. Adv. 4, eaap9004. 10.1126/sciadv.aap900410.1126/sciadv.aap9004PMC579679529404407Long C., McAnally J. R., Shelton J. M., Mireault A. A., Bassel-Duby R., Olson E. N. (2014). Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science 345, 1184–1188. 10.1126/science.125444510.1126/science.1254445PMC439802725123483Lostal W., Kodippili K., Yue Y., Duan D. (2014). Full-length dystrophin reconstitution with adeno-associated viral vectors. Hum. Gene Ther. 25, 552–562. 10.1089/hum.2013.21010.1089/hum.2013.210PMC406472624580018Love D. R., Hillt D. F., Dicksont G., Spurr N. K., Byth B. C., Marsden R. F., et al. (1989). An autosomal transcript in skeletal muscle with homology to dystrophin. Nature 339, 55–58. 10.1038/339055a010.1038/339055a02541343Lozanoska-Ochser B., Benedetti A., Rizzo G., Marrocco V., di Maggio R., Fiore P., et al. (2018). Targeting early PKCθ-dependent T-cell infiltration of dystrophic muscle reduces disease severity in a mouse model of muscular dystrophy. J. Pathol. 244, 323–333. 10.1002/path.501610.1002/path.501629214629Lu Q. L., Mann C. J., Lou F., Bou-Gharios G., Morris G. E., Xue S. A., et al. (2003). Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nat. Med. 9, 1009–1014. 10.1038/nm89710.1038/nm89712847521Ma N., Chen D., Lee J. H., Kuri P., Hernandez E. B., Kocan J., et al. (2022). Piezo1 regulates the regenerative capacity of skeletal muscles via orchestration of stem cell morphological states. Sci. Adv. 8, eabn0485. 10.1126/sciadv.abn048510.1126/sciadv.abn0485PMC893265735302846Maffioletti S. M., Noviello M., English K., Tedesco F. S. (2014). Stem cell transplantation for muscular dystrophy: The challenge of immune response. Biomed. Res. Int. 2014, 964010–964012. 10.1155/2014/96401010.1155/2014/964010PMC409861325054157Maggio I., Liu J., Janssen J. M., Chen X., Goncalves M. A. (2016a). Adenoviral vectors encoding CRISPR/Cas9 multiplexes rescue dystrophin synthesis in unselected populations of DMD muscle cells. Sci. Rep. 6, 37051. 10.1038/srep3705110.1038/srep37051PMC510924527845387Maggio I., Stefanucci L., Janssen J. M., Liu J., Chen X., Mouly V., et al. (2016b). Selection-free gene repair after adenoviral vector transduction of designer nucleases: Rescue of dystrophin synthesis in DMD muscle cell populations. Nucleic Acids Res. 44, 1449–1470. 10.1093/nar/gkv154010.1093/nar/gkv1540PMC475684326762977 Maino E., Wojtal D., Evagelou S. L., Farheen A., Wong T. W. Y., Lindsay K., et al. (2021). Targeted genome editing in vivo corrects a Dmd duplication restoring wild-type dystrophin expression. EMBO Mol. Med. 13, e13228. 10.15252/emmm.202013228 10.15252/emmm.202013228PMC810308633724658Makarova K. S., Wolf Y. I., Iranzo J., Shmakov S. A., Alkhnbashi O. S., Brouns S. J. J., et al. (2020). Evolutionary classification of CRISPR-cas systems: A burst of class 2 and derived variants. Nat. Rev. Microbiol. 18, 67–83. 10.1038/s41579-019-0299-x10.1038/s41579-019-0299-xPMC890552531857715Malerba A., Boldrin L., Dickson G. (2011). Long-term systemic administration of unconjugated morpholino oligomers for therapeutic expression of dystrophin by exon skipping in skeletal muscle: Implications for cardiac muscle integrity. Nucleic Acid. Ther. 21, 293–298. 10.1089/nat.2011.030610.1089/nat.2011.030621851223Mali P., Yang L., Esvelt K. M., Aach J., Guell M., DiCarlo J. E., et al. (2013). RNA-guided human genome engineering via Cas9. Science 339, 823–826. 10.1126/science.123203310.1126/science.1232033PMC371262823287722Malik V., Rodino-Klapac L. R., Viollet L., Wall C., King W., Al-Dahhak R., et al. (2010). Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann. Neurol. 67, 771–780. 10.1002/ana.2202410.1002/ana.2202420517938Mamchaoui K. (2018). Myoblots: Dystrophin quantification by in-cell Western assay for a streamlined development of duchenne muscular dystrophy (DMD) treatments. Neuropathol. Appl. Neurobiol. 44, 463–473. 10.1111/nan.1244810.1111/nan.1244829086434Mann C. J., Honeyman K., Cheng A. J., Ly T., Lloyd F., Fletcher S., et al. (2001). Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse. Proc. Natl. Acad. Sci. U. S. A. 98, 42–47. 10.1073/pnas.01140859810.1073/pnas.011408598PMC1454111120883Mareedu S., Million E. D., Duan D., Babu G. J. (2021). Abnormal calcium handling in duchenne muscular dystrophy: Mechanisms and potential therapies. Front. Physiol. 12, 647010–647019. 10.3389/fphys.2021.64701010.3389/fphys.2021.647010PMC806304933897454Markham B. E., Kernodle S., Nemzek J., Wilkinson J. E., Sigler R. (2015). Chronic dosing with membrane sealant poloxamer 188 NF improves respiratory dysfunction in dystrophic mdx and mdx/utrophin-/- mice. PLoS One 10, e0134832. 10.1371/journal.pone.013483210.1371/journal.pone.0134832PMC452769526248188Mata López S., Balog-Alvarez C., Vitha S., Bettis A. K., Canessa E. H., Kornegay J. N., et al. (2020). Challenges associated with homologous directed repair using CRISPR-Cas9 and TALEN to edit the DMD genetic mutation in canine Duchenne muscular dystrophy. PLoS One 15, e0228072. 10.1371/journal.pone.022807210.1371/journal.pone.0228072PMC697417231961902Matre P. R., Mu X., Wu J., Danila D., Hall M. A., Kolonin M. G., et al. (2019). CRISPR/Cas9-Based dystrophin restoration reveals a novel role for dystrophin in bioenergetics and stress resistance of muscle progenitors. Stem Cells 37, 1615–1628. 10.1002/stem.309410.1002/stem.3094PMC691663631574188Mauro A. (1961). Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol. 9, 493–495. 10.1083/jcb.9.2.49310.1083/jcb.9.2.493PMC222501213768451Mayer U., Saher G., Fassler R., Bornemann A., Echtermeyer F., Mark H. V. D., et al. (1997). Absence of integrin alpha 7 causes a novel form of muscular dystrophy. Nat. Genet. 17 (3), 318–323. 10.1038/ng1197-31810.1038/ng1197-3189354797Mázala D. A. G., Novak J. S., Hogarth M. W., Nearing M., Adusumalli P., Tully C. B., et al. (2020). TGF-β–driven muscle degeneration and failed regeneration underlie disease onset in a DMD mouse model. JCI Insight 5, e135703. 10.1172/jci.insight.13570310.1172/jci.insight.135703PMC721379832213706 McCourt J. L., Rhett K. K., Jaeger M. A., Belanto J. J., Talsness D. M., Ervasti J. M. (2015). In vitro stability of therapeutically relevant, internally truncated dystrophins. Skelet. Muscle 5, 13. 10.1186/s13395-015-0040-z 10.1186/s13395-015-0040-zPMC442417425954502McDonald C. M., Henricson E. K., Abresch R. T., Duong T., Joyce N. C., Hu F., et al. (2018). Long-term effects of glucocorticoids on function, quality of life, and survival in patients with duchenne muscular dystrophy: A prospective cohort study. Lancet 391, 451–461. 10.1016/S0140-6736(17)32160-810.1016/S0140-6736(17)32160-829174484McDonald C. M., Marbán E., Hendrix S., Hogan N., Ruckdeschel Smith R., Eagle M., et al. (2022). Repeated intravenous cardiosphere-derived cell therapy in late-stage duchenne muscular dystrophy (HOPE-2): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 399, 1049–1058. 10.1016/S0140-6736(22)00012-510.1016/S0140-6736(22)00012-535279258McDonald C. M., Sajeev G., Yao Z., McDonnell E., Elfring G., Souza M., et al. (2020). Deflazacort vs prednisone treatment for duchenne muscular dystrophy: A meta-analysis of disease progression rates in recent multicenter clinical trials. Muscle Nerve 61, 26–35. 10.1002/mus.2673610.1002/mus.26736PMC697328931599456McDonald D. G. M., Kinali M., Gallagher A. C., Mercuri E., Muntoni F., Frcpch H. R., et al. (2002). Fracture prevalence in Duchenne muscular dystrophy. Dev. Med. Child. Neurol. 44, 695–698. 10.1017/s001216220100277810.1017/s001216220100277812418795McElroy S. P., Nomura T., Torrie L. S., Warbrick E., Gartner U., Wood G., et al. (2013). A lack of premature termination codon read-through efficacy of PTC124 (ataluren) in a diverse array of reporter assays. PLoS Biol. 11, e1001593. 10.1371/journal.pbio.100159310.1371/journal.pbio.1001593PMC369244523824517Mcmahon C. D., Popovic L., Oldham J. M., Jeanplong F., Smith H. K., Kambadur R., et al. (2022). Myostatin-deficient mice lose more skeletal muscle mass than wild-type controls during hindlimb suspension, 82–87.12618358McNally E. M., Pytel P. (2007). Muscle diseases: The muscular dystrophies. Annu. Rev. Pathol. 2, 87–109. 10.1146/annurev.pathol.2.010506.09193610.1146/annurev.pathol.2.010506.09193618039094McNally E. M., Wyatt E. J. (2017). Mutation-based therapy for duchenne muscular dystrophy: Antisense treatment arrives in the clinic. Circulation 136, 979–981. 10.1161/CIRCULATIONAHA.117.02838210.1161/CIRCULATIONAHA.117.028382PMC565758928893959McNally E. (2012). Novel targets and approaches to treating skeletal muscle disease. First Edit. Elsevier Inc. 10.1016/B978-0-12-381510-1.00081-810.1016/B978-0-12-381510-1.00081-8Mcpherron A. C., Lawlert A. M., Lee S. (1997). Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 38711, 83–90. 10.1038/387083a010.1038/387083a09139826Mead A. F., Petrov M., Malik A. S., Mitchell M. A., Childers M. K., Bogan J. R., et al. (2014). Diaphragm remodeling and compensatory respiratory mechanics in a canine model of Duchenne muscular dystrophy. J. Appl. Physiol. 116, 807–815. 10.1152/japplphysiol.00833.201310.1152/japplphysiol.00833.2013PMC397275124408990 Mendell J. R., Al-zaidy S. A., Rodino-klapac L. R., Goodspeed K., Gray S. J., Kay C. N., et al. (2021). Current clinical applications of in vivo gene therapy with AAVs. Mol. Ther. 29, 464–488. 10.1016/j.ymthe.2020.12.007 10.1016/j.ymthe.2020.12.007PMC785429833309881Mendell J. R., Al-Zaidy S., Shell R., Arnold W. D., Rodino-Klapac L. R., Prior T. W., et al. (2017). Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722. 10.1056/nejmoa170619810.1056/nejmoa170619829091557Mendell J. R., Campbell K., Rodino-Klapac L., Sahenk Z., Shilling C., Lewis S., et al. (2010). Dystrophin immunity in duchenne’s muscular dystrophy. N. Engl. J. Med. 363, 1429–1437. 10.1056/nejmoa100022810.1056/nejmoa1000228PMC301410620925545Mendell J. R., Goemans N., Lowes L. P., Alfano L. N., Berry K., Shao J., et al. (2016). Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. 10.1002/ana.2455510.1002/ana.24555PMC506475326573217Mendell J. R., Sahenk Z., Lehman K., Nease C., Lowes L. P., Miller N. F., et al. (2020). Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in children with duchenne muscular dystrophy: A nonrandomized controlled trial. JAMA Neurol. 77, 1122–1131. 10.1001/jamaneurol.2020.148410.1001/jamaneurol.2020.1484PMC729646132539076Mendell J. R., Shilling C., Leslie N. D., Flanigan K. M., Al-Dahhak R., Gastier-Foster J., et al. (2012). Evidence-based path to newborn screening for duchenne muscular dystrophy. Ann. Neurol. 71, 304–313. 10.1002/ana.2352810.1002/ana.2352822451200Meng X. M., Nikolic-Paterson D. J., Lan H. Y. (2016). TGF-Β: The master regulator of fibrosis. Nat. Rev. Nephrol. 12, 325–338. 10.1038/nrneph.2016.4810.1038/nrneph.2016.4827108839Merchant F. A., Holmes W. H., Capelli-Schellpfeffer M., Lee R. C., Toner M. (1998). Poloxamer 188 enhances functional recovery of lethally heat-shocked fibroblasts. J. Surg. Res. 74, 131–140. 10.1006/jsre.1997.525210.1006/jsre.1997.52529587351Mercuri E., Bönnemann C. G., Muntoni F. (2019). Muscular dystrophies. Lancet 394, 2025–2038. 10.1016/S0140-6736(19)32910-110.1016/S0140-6736(19)32910-131789220Mercuri E., Muntoni F. (2013). Muscular dystrophies. Lancet 381, 845–860. 10.1016/S0140-6736(12)61897-210.1016/S0140-6736(12)61897-223465426Meyer G. A., Lieber R. L. (2011). Elucidation of extracellular matrix mechanics from muscle fibers and fiber bundles. J. Biomech. 44, 771–773. 10.1016/j.jbiomech.2010.10.04410.1016/j.jbiomech.2010.10.044PMC304251721092966Meyers T. A., Townsend D. W. (2019). Cardiac pathophysiology and the future of cardiac therapies in duchenne muscular dystrophy. Int. J. Mol. Sci. 20, 4098. 10.3390/ijms2017409810.3390/ijms20174098PMC674738331443395Michel R. N., Chakkalakal J. V., Miura P., Be G., Jasmin B. J. (2008). Modulation of utrophin A mRNA stability in fast versus slow muscles via an AU-rich element and calcineurin signaling. Nucleic Acids Res. 36, 826–838. 10.1093/nar/gkm110710.1093/nar/gkm1107PMC224190818084024 Miller J. B., Zhang S., Kos P., Xiong H., Zhou K., Perelman S. S., et al. (2017). Non-viral CRISPR/Cas gene editing in vitro and in vivo enabled by synthetic nanoparticle Co-delivery of Cas9 mRNA and sgRNA. Angew. Chem. Int. Ed. Engl. 56, 1059–1063. 10.1002/anie.201610209 10.1002/anie.201610209PMC552101127981708Min Y. L., Bassel-Duby R., Olson E. N. (2019a). CRISPR correction of duchenne muscular dystrophy. Annu. Rev. Med. 70, 239–255. 10.1146/annurev-med-081117-01045110.1146/annurev-med-081117-010451PMC641569330379597Min Y. L., Li H., Rodriguez-Caycedo C., Mireault A. A., Huang J., Shelton J. M., et al. (2019b). CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. Sci. Adv. 5, eaav4324. 10.1126/sciadv.aav432410.1126/sciadv.aav4324PMC640284930854433Mitrpant C., Fletcher S., Iversen P. L., Wilton S. D. (2009). By‐passing the nonsense mutation in the 4CV mouse model of muscular dystrophy by induced exon skipping. J. Gene Med. A cross‐disciplinary J. Res. Sci. gene Transf. its Clin. Appl. 11, 46–56. 10.1002/jgm.126510.1002/jgm.126519006096Moe K. T., Yin N. O., Naylynn T. M., Khairunnisa K., Wutyi M. A., Gu Y., et al. (2011). Nox2 and Nox4 mediate tumour necrosis factor-alpha-induced ventricular remodelling in mice. J. Cell Mol. Med. 15, 2601–2613. 10.1111/j.1582-4934.2011.01261.x10.1111/j.1582-4934.2011.01261.xPMC437342921251215Mojumdar K., Liang F., Giordano C., Lemaire C., Danialou G., Okazaki T., et al. (2014). Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2. EMBO Mol. Med. 6, 1476–1492. 10.15252/emmm.20140396710.15252/emmm.201403967PMC423747225312642Mokri B., Engel A. G. (1975). Duchenne dystrophy: Electron microscopic findings pointing to a basic or early abnormality in the plasma membrane of the muscle fiber. Neurology 25, 1111–1120. 10.1212/wnl.25.12.111110.1212/wnl.25.12.11111105232Montanaro F., Lindenbaum M., Carbonetto S. (1999). alpha-Dystroglycan is a laminin receptor involved in extracellular matrix assembly on myotubes and muscle cell viability. J. Cell Biol. 145, 1325–1340. 10.1083/jcb.145.6.132510.1083/jcb.145.6.1325PMC213314610366602Moore T. M., Lin A. J., Strumwasser A. R., Cory K., Whitney K., Ho T., et al. (2020). Mitochondrial dysfunction is an early consequence of partial or complete dystrophin loss in mdx mice. Front. Physiol. 11, 690. 10.3389/fphys.2020.0069010.3389/fphys.2020.00690PMC731702132636760Moorwood C., Lozynska O., Suri N., Napper A. D., Diamond S. L., Khurana T. S. (2011). Drug discovery for Duchenne muscular dystrophy via utrophin promoter activation screening. Utrophin Promot. Act. Screen. 6, 261699–e26211. 10.1371/journal.pone.0026169 via10.1371/journal.pone.0026169PMC319761422028826Moretti A., Fonteyne L., Giesert F., Hoppmann P., Meier A. B., Bozoglu T., et al. (2020). Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy. Nat. Med. 26, 207–214. 10.1038/s41591-019-0738-210.1038/s41591-019-0738-2PMC721206431988462Morgan J., Muntoni F. (2021). Changes in myonuclear number during postnatal growth–implications for AAV gene therapy for muscular dystrophy. J. Neuromuscul. Dis. 1–8, S317–S324. 10.3233/JND-21068310.3233/JND-210683PMC867349434334413Moss F. P., Leblond C. P. (1971). Satellite cells as the source of nuclei in muscles of growing rats. Anat. Rec. 170, 421–435. 10.1002/ar.109170040510.1002/ar.10917004055118594Mulivor A., Cannell M., Davies M., Sako D., Liu J., Bresnahan D., et al. (2014). “ACE-083, a ligand trap for members of the TGFβ superfamily, increases muscle mass locally in a mouse model of Duchenne muscular dystrophy,” in Presented at action Duchenne int. Conf., 12th, london, nov, 7–8.Mullard A. (2021a). N E W S and A N A LY S I S News in BRieF FDA outlines steps for individualized drug development. Nat. Rev. Drug Discov. 20 (2), 91. 10.1038/d41573-021-00009-710.1038/d41573-021-00009-733441996Mullard A. (2021b). N E W S and A N A LY S I S News in BRieF FDA outlines steps for individualized drug development. Nat. Rev. Drug Discov. 20, 6939926.33441996Muntoni F., Tejura B., Spinty S., Roper H., Hughes I., Layton G., et al. (2019). A phase 1b trial to assess the pharmacokinetics of Ezutromid in pediatric duchenne muscular dystrophy patients on a balanced diet. Clin. Pharmacol. Drug Dev. 8, 922–933. 10.1002/cpdd.64210.1002/cpdd.64230650257Nallamilli B. R. R., Chaubey A., Valencia C. A., Stansberry L., Behlmann A. M., Ma Z., et al. (2021). A single NGS-based assay covering the entire genomic sequence of the DMD gene facilitates diagnostic and newborn screening confirmatory testing. Hum. Mutat. 42, 626–638. 10.1002/humu.2419110.1002/humu.2419133644936 Nelson C. E., Hakim C. H., Ousterout D. G., Thakore P. I., Moreb E. A., Castellanos Rivera R. M., et al. (2016). In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351, 403–407. 10.1126/science.aad5143 10.1126/science.aad5143PMC488359626721684Nelson C. E., Robinson-Hamm J. N., Gersbach C. A. (2017). Genome engineering: A new approach to gene therapy for neuromuscular disorders. Nat. Rev. Neurol. 13, 647–661. 10.1038/nrneurol.2017.12610.1038/nrneurol.2017.12628960187Nelson C. E., Wu Y., Gemberling M. P., Oliver M. L., Waller M. A., Bohning J. D., et al. (2019). Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nat. Med. 25, 427–432. 10.1038/s41591-019-0344-310.1038/s41591-019-0344-3PMC645597530778238Nelson D. M., Lindsay A., Judge L. M., Duan D., Chamberlain J. S., Lowe D. A., et al. (2018). Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins. Hum. Mol. Genet. 27, 2090–2100. 10.1093/hmg/ddy11310.1093/hmg/ddy113PMC598572329618008Nguyen Q., Yokota T. (2019). Antisense oligonucleotides for the treatment of cardiomyopathy in duchenne muscular dystrophy. Am. J. Transl. Res. 11, 1202–1218.PMC645650730972156Niks E. H., Aartsma-Rus A. (2017). Exon skipping: A first in class strategy for duchenne muscular dystrophy. Expert Opin. Biol. Ther. 17, 225–236. 10.1080/14712598.2017.127187210.1080/14712598.2017.127187227936976Nishi M., Yasue A., Nishimatu S., Nohno T., Yamaoka T., Itakura M., et al. (2002). A missense mutant myostatin causes hyperplasia without hypertrophy in the mouse muscle. hypertrophy mouse muscle 293, 247–251. 10.1016/S0006-291X(02)00209-710.1016/S0006-291X(02)00209-712054591Nishida K., Arazoe T., Yachie N., Banno S., Kakimoto M., Tabata M., et al. (2016). Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems. Science 353, aaf8729. 10.1126/science.aaf872910.1126/science.aaf872927492474Novak J. S., Hogarth M. W., Boehler J. F., Nearing M., Vila M. C., Heredia R., et al. (2017). Myoblasts and macrophages are required for therapeutic morpholino antisense oligonucleotide delivery to dystrophic muscle. Nat. Commun. 8, 941. 10.1038/s41467-017-00924-710.1038/s41467-017-00924-7PMC564339629038471Odom G. L., Gregorevic P., Chamberlain J. S. (2007). Viral-mediated gene therapy for the muscular dystrophies: Successes, limitations and recent advances. Biochim. Biophys. Acta 1772, 243–262. 10.1016/j.bbadis.2006.09.00710.1016/j.bbadis.2006.09.007PMC189491017064882Olson E. N. (2021). Toward the correction of muscular dystrophy by gene editing. Proc. Natl. Acad. Sci. U. S. A. 118, e2004840117. 10.1073/pnas.200484011710.1073/pnas.2004840117PMC817916434074727Onopiuk M., Brutkowski W., Wierzbicka K., Wojciechowska S., Szczepanowska J., Fronk J., et al. (2009). Mutation in dystrophin-encoding gene affects energy metabolism in mouse myoblasts. Biochem. Biophys. Res. Commun. 386, 463–466. 10.1016/j.bbrc.2009.06.05310.1016/j.bbrc.2009.06.05319527684Ousterout D. G., Kabadi A. M., Thakore P. I., Majoros W. H., Reddy T. E., Gersbach C. A. (2015). Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. Nat. Commun. 6, 6244. 10.1038/ncomms724410.1038/ncomms7244PMC433535125692716Pant M., Sopariwala D. H., Bal N. C., Lowe J., Delfin D. A., Rafael-Fortney J., et al. (2015). Metabolic dysfunction and altered mitochondrial dynamics in the utrophin-dystrophin deficient mouse model of duchenne muscular dystrophy. PLoS One 10, e0123875. 10.1371/journal.pone.012387510.1371/journal.pone.0123875PMC439325725859846Papa S., Skulachev V. P. (1997). Reactive oxygen species, mitochondria, apoptosis and aging. Mol. Cell Biochem. 174, 305–319. 10.1023/A:100687351842710.1023/A:10068735184279309704Passaquin A. C., Renard M., Kay L., Challet C., Mokhtarian A., Wallimann T., et al. (2002). Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice. Neuromuscul. Disord. 12, 174–182. 10.1016/s0960-8966(01)00273-510.1016/s0960-8966(01)00273-511738360Percival J. M., Siegel M. P., Knowels G., Marcinek D. J. (2013). Defects in mitochondrial localization and ATP synthesis in the mdx mouse model of Duchenne muscular dystrophy are not alleviated by PDE5 inhibition. Hum. Mol. Genet. 22, 153–167. 10.1093/hmg/dds41510.1093/hmg/dds415PMC352240423049075Perez-Pinera P., Kocak D. D., Vockley C. M., Adler A. F., Kabadi A. M., Polstein L. R., et al. (2013). RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat. Methods 10, 973–976. 10.1038/Nmeth.260010.1038/Nmeth.2600PMC391178523892895Pertille A., De Carvalho C. L. T., Matsumura C. Y., Neto H. S., Marques M. J. (2010). Calcium-binding proteins in skeletal muscles of the mdx mice: Potential role in the pathogenesis of Duchenne muscular dystrophy. Int. J. Exp. Pathol. 91, 63–71. 10.1111/j.1365-2613.2009.00688.x10.1111/j.1365-2613.2009.00688.xPMC281272920002835Pescatori M., Broccolini A., Minetti C., Bertini E., Bruno C., D’amico A., et al. (2007). Gene expression profiling in the early phases of DMD: A constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression. FASEB J. 21, 1210–1226. 10.1096/fj.06-7285com10.1096/fj.06-7285com17264171Pestronk A., Parhad I., Drachman D., Price D. L. (1982). Membrane myopathy: Morphological similarities to duchenne muscular dystrophy. Muscle Nerve 5, 209–214. 10.1002/mus.88005030610.1002/mus.8800503067088018Petrillo S., Pelosi L., Piemonte F., Travaglini L., Forcina L., Catteruccia M., et al. (2017). Oxidative stress in duchenne muscular dystrophy: Focus on the NRF2 redox pathway. Hum. Mol. Genet. 26, 2781–2790. 10.1093/hmg/ddx17310.1093/hmg/ddx17328472288Petrof B. J., Shrager J. B., Stedman H. H., Kelly A. M., Sweeney H. L. (1993). Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc. Natl. Acad. Sci. U. S. A. 90, 3710–3714. 10.1073/pnas.90.8.371010.1073/pnas.90.8.3710PMC463718475120 Pfizer (2014). Pfizer initiates phase 2 study of PF-06252616 in Duchenne muscular dystrophy. Press Release. Dec. 17 Available at: http://www.pfizer.com/news/press-release/press-release-detail/pfizer_initiates_phase_.2_study_of_pf_06252616_in_duchenne_muscular_dystrophy .Phelps S. F., Hauser M. A., Cole N. M., Rafael J. A., Hinkle R. T., Faulkner J. A., et al. (1995). Expression of full-length and truncated dystrophin mini-genes in transgenic mdx mice. Hum. Mol. Genet. 4, 1251–1258. 10.1093/hmg/4.8.125110.1093/hmg/4.8.12517581361Pickar-Oliver A., Gough V., Bohning J. D., Liu S., Robinson-Hamm J. N., Daniels H., et al. (2021). Full-length dystrophin restoration via targeted exon integration by AAV-CRISPR in a humanized mouse model of Duchenne muscular dystrophy. Mol. Ther. 29, 3243–3257. 10.1016/j.ymthe.2021.09.00310.1016/j.ymthe.2021.09.003PMC857116834509668Pinniger G. J., Terrill J. R., Assan E. B., Grounds M. D., Arthur P. G. (2017). Pre-clinical evaluation of N-acetylcysteine reveals side effects in the mdx mouse model of Duchenne muscular dystrophy. J. Physiol. 595, 7093–7107. 10.1113/JP27422910.1113/JP274229PMC570933328887840Politano L., Nigro G., Nigro V., Pilus G., Papparella S., Paciello O., et al. (2003). Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results. Acta Myol. 22, 15–21.12966700Politano L. (2021). Read-through approach for stop mutations in Duchenne muscular dystrophy. An update. update 12, 43–50. 10.36185/2532-1900-04110.36185/2532-1900-041PMC803342433870095Pons F., Nicholson L. V., Robert A., Voit T., Leger J. J. (1993). Dystrophin and dystrophin-related protein (utrophin) distribution in normal and dystrophin-deficient skeletal muscles. Neuromuscul. Disord. 3, 507–514. 10.1016/0960-8966(93)90106-t10.1016/0960-8966(93)90106-t8186702Powers S. K., Ji L. L., Kavazis A. N., Jackson M. J. (2011). Reactive oxygen species: Impact on skeletal muscle. Compr. Physiol. 1, 941–969. 10.1002/cphy.c10005410.1002/cphy.c100054PMC389311623737208Prayle A., Smyth A. R. (2010). Aminoglycoside use in cystic fibrosis: Therapeutic strategies and toxicity. Curr. Opin. Pulm. Med. 16, 604–610. 10.1097/MCP.0b013e32833eebfd10.1097/MCP.0b013e32833eebfd20814306Qi L. S., Larson M. H., Gilbert L. A., Doudna J. A., Weissman J. S., Arkin A. P., et al. (2013). Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152, 1173–1183. 10.1016/j.cell.2013.02.02210.1016/j.cell.2013.02.022PMC366429023452860Rafael J. A., Cox G. A., Corrado K., Jung D., Campbell K. P., Chamberlain J. S. (1996). Forced expression of dystrophin deletion constructs reveals structure-function correlations. J. Cell Biol. 134, 93–102. 10.1083/jcb.134.1.9310.1083/jcb.134.1.93PMC21209128698825Ramos J. N., Hollinger K., Bengtsson N. E., Allen J. M., Hauschka S. D., Chamberlain J. S. (2019). Development of novel micro-dystrophins with enhanced functionality. Mol. Ther. 27, 623–635. 10.1016/j.ymthe.2019.01.00210.1016/j.ymthe.2019.01.002PMC640348530718090Ran F. A., Hsu P. D., Lin C. Y., Gootenberg J. S., Konermann S., Trevino A. E., et al. (2013). Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154, 1380–1389. 10.1016/j.cell.2013.08.02110.1016/j.cell.2013.08.021PMC385625623992846Reid M. B. (2001). Invited review: Redox modulation of skeletal muscle contraction: What we know and what we don’t. J. Appl. Physiol. 90, 724–731. 10.1152/jappl.2001.90.2.72410.1152/jappl.2001.90.2.72411160074Reid M. B., Shoji T., Moody M. R., Entman M. L. (1992). Reactive oxygen in skeletal muscle. II. Extracellular release of free radicals. J. Appl. Physiol. 73, 1805–1809. 10.1152/jappl.1992.73.5.180510.1152/jappl.1992.73.5.18051335453Reisz-porszasz S., Bhasin S., Artaza J. N., Shen R., Sinha-hikim I., Hogue A., et al. (2022). Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin, 876–888.12824080Ricotti V., Spinty S., Roper H., Hughes I., Tejura B., Robinson N., et al. (2016). Safety, tolerability, and pharmacokinetics of SMT C1100, a 2-arylbenzoxazole utrophin modulator, following single- and multiple- dose administration to pediatric patients with duchenne muscular dystrophy. PLoS One. 11, 1–16. 10.1371/journal.pone.015284010.1371/journal.pone.0152840PMC482438427055247Rimessi P., Sabatelli P., Fabris M., Braghetta P., Bassi E., Spitali P., et al. (2009). Cationic PMMA nanoparticles bind and deliver antisense oligoribonucleotides allowing restoration of dystrophin expression in the mdx mouse. Mol. Ther. 17, 820–827. 10.1038/mt.2009.810.1038/mt.2009.8PMC283512719240694Roberts R. G., Coffey A. J., Bobrow M., Bentley D. R. (1993). Exon structure of the human dystrophin gene. Genomics 16, 536–538. 10.1006/geno.1993.122510.1006/geno.1993.12258314593Rogers G. L., Martino A. T., Aslanidi G. V., Jayandharan G. R., Srivastava A., Herzog R. W. (2011). Innate immune responses to AAV vectors. Front. Microbiol. 2, 194. 10.3389/fmicb.2011.0019410.3389/fmicb.2011.00194PMC317561321954398Rong Z., Fu X., Wang M., Xu Y. (2012). A scalable approach to prevent teratoma formation of human embryonic stem cells. J. Biol. Chem. 287, 32338–32345. 10.1074/jbc.M112.38381010.1074/jbc.M112.383810PMC346333022865887Rooney J. E., Gurpur P. B., Burkin D. J. (2009a). Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy, 106.PMC268311319416897Rooney J. E., Gurpur P. B., Yablonka-reuveni Z., Burkin D. J. (2009b). Laminin-111 restores regenerative capacity in a mouse model for alpha7 integrin congenital myopathy. Am. J. Pathol. 174, 256–264. 10.2353/ajpath.2009.08052210.2353/ajpath.2009.080522PMC263133819074617Rooney J. E., Welser J. V., Dechert M. A., Flintoff-dye N. L., Kaufman S. J., Burkin D. J. (2006). Severe muscular dystrophy in mice that lack dystrophin and 7 integrin. 10.1242/jcs.0295210.1242/jcs.0295216684813Rosenberg A. S., Puig M., Nagaraju K., Hoffman E. P., Villalta S. A., Rao V. A., et al. (2015). Immune-mediated pathology in Duchenne muscular dystrophy. Sci. Transl. Med. 7, 299rv4. 10.1126/scitranslmed.aaa732210.1126/scitranslmed.aaa7322PMC595138026246170Rouger K., Larcher T., Dubreil L., Deschamps J.-Y., le Guiner C., Jouvion G., et al. (2011). Systemic delivery of allogenic muscle stem cells induces long-term muscle repair and clinical efficacy in duchenne muscular dystrophy dogs. Am. J. Pathol. 179, 2501–2518. 10.1016/j.ajpath.2011.07.02210.1016/j.ajpath.2011.07.022PMC320408821924229Rybakova I. N., Amann K. J., Ervasti J. M. (1996). A new model for the interaction of dystrophin with F-actin. J. Cell Biol. 135, 661–672. 10.1083/jcb.135.3.66110.1083/jcb.135.3.661PMC21210718909541Ryu S. M., Koo T., Kim K., Lim K., Baek G., Kim S. T., et al. (2018). Adenine base editing in mouse embryos and an adult mouse model of Duchenne muscular dystrophy. Nat. Biotechnol. 36, 536–539. 10.1038/nbt.414810.1038/nbt.414829702637 Saclier M., ben Larbi S., My Ly H., Moulin E., Mounier R., Chazaud B., et al. (2021). Interplay between myofibers and pro-inflammatory macrophages controls muscle damage in mdx mice. J. Cell Sci. 134, jcs258429. 10.1242/jcs.258429 10.1242/jcs.25842934471933Saleh A. F., Arzumanov A. A., Gait M. J. (2012). “Overview of alternative oligonucleotide chemistries for exon skipping,” in Exon skipping: Methods and protocols. Editor Aartsma-Rus A. (Totowa, NJ: Humana Press; ), 365–378. 10.1007/978-1-61779-767-5_2310.1007/978-1-61779-767-5_2322454073Salva M. Z., Himeda C. L., Tai P. W., Nishiuchi E., Gregorevic P., Allen J. M., et al. (2007). Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Mol. Ther. 15, 320–329. 10.1038/sj.mt.630002710.1038/sj.mt.630002717235310Schneider A. E., Aartsma-Rus A. (2021). Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy. Expert Opin. Biol. Ther. 21, 343–359. 10.1080/14712598.2021.183246210.1080/14712598.2021.183246233074029Schnepp B. C., Clark K. R., Klemanski D. L., Pacak C. A., Johnson P. R. (2003). Genetic fate of recombinant adeno-associated virus vector genomes in muscle. J. Virol. 77, 3495–3504. 10.1128/jvi.77.6.3495-3504.200310.1128/jvi.77.6.3495-3504.2003PMC14953012610125Schuh R. A., Jackson K. C., Khairallah R. J., Ward C. W., Spangenburg E. E. (2012). Measuring mitochondrial respiration in intact single muscle fibers. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R712–R719. 10.1152/ajpregu.00229.201110.1152/ajpregu.00229.2011PMC377448522160545Sciorati C., Rigamonti E., Manfredi A. A., Rovere-Querini P. (2016). Cell death, clearance and immunity in the skeletal muscle. Cell Death Differ. 23, 927–937. 10.1038/cdd.2015.17110.1038/cdd.2015.171PMC498772826868912Sharma G., Sharma A. R., Bhattacharya M., Lee S. S., Chakraborty C. (2021). CRISPR-Cas9: A preclinical and clinical perspective for the treatment of human diseases. Mol. Ther. 29, 571–586. 10.1016/j.ymthe.2020.09.02810.1016/j.ymthe.2020.09.028PMC785428433238136Sheikh O., Yokota T. (2021). Restoring protein expression in neuromuscular conditions: A review assessing the current state of exon skipping/inclusion and gene therapies for duchenne muscular dystrophy and spinal muscular atrophy. BioDrugs 35, 389–399. 10.1007/s40259-021-00486-710.1007/s40259-021-00486-734097287Sinadinos A., Young C. N. J., Al-Khalidi R., Teti A., Kalinski P., Mohamad S., et al. (2015). P2RX7 purinoceptor: A therapeutic target for ameliorating the symptoms of duchenne muscular dystrophy. PLoS Med. 12, e1001888. 10.1371/journal.pmed.100188810.1371/journal.pmed.1001888PMC460407826461208Skuk D., Goulet M., Roy B., Chapdelaine P., Bouchard J.-P., Roy R., et al. (2006). Dystrophin expression in muscles of duchenne muscular dystrophy patients after high-density injections of normal myogenic cells. J. Neuropathol. Exp. Neurol. 65, 371–386. 10.1097/01.jnen.0000218443.45782.8110.1097/01.jnen.0000218443.45782.8116691118Skuk D., Roy B., Goulet M., Chapdelaine P., Bouchard J.-P., Roy R., et al. (2004). Dystrophin expression in myofibers of duchenne muscular dystrophy patients following intramuscular injections of normal myogenic cells. Mol. Ther. 9, 475–482. 10.1016/j.ymthe.2003.11.02310.1016/j.ymthe.2003.11.02315038390Smythe G. M., Hodgetts S. I., Grounds M. D. (2000). Immunobiology and the future of myoblast transfer therapy. Mol. Ther. 1, 304–313. 10.1006/mthe.2000.004910.1006/mthe.2000.004910933948Soblechero-Martín P., López-Martínez A., de la Puente-Ovejero L., Vallejo-Illarramendi A., Arechavala-Gomeza V. (2021). Utrophin modulator drugs as potential therapies for Duchenne and Becker muscular dystrophies. Neuropathol. Appl. Neurobiol. 47, 711–723. 10.1111/nan.1273510.1111/nan.12735PMC851836833999469Sonnemann K. J., Heun-johnson H., Turner A. J., Baltgalvis K. A., Lowe D. A., Ervasti J. M. (2009). Functional substitution by TAT-utrophin in dystrophin- deficient mice. PLoS Med. 6, e1000083. 10.1371/journal.pmed.100008310.1371/journal.pmed.1000083PMC268062019478831Sorichter S., Mair J., Koller A., Pelsers M. M., Puschendorf B., Glatz J. F. (1998). Early assessment of exercise induced skeletal muscle injury using plasma fatty acid binding protein. Br. J. Sports Med. 32, 121–124. 10.1136/bjsm.32.2.12110.1136/bjsm.32.2.121PMC17560909631217Sorichter S., Puschendorf B., Mair J. (1999). Skeletal muscle injury induced by eccentric muscle action: Muscle proteins as markers of muscle fiber injury. Exerc Immunol. Rev. 5, 5–21.10519060Spencer M. J., Montecino-Rodriguez E., Dorshkind K., Tidball J. G. (2001). Helper (CD4+) and cytotoxic (CD8+) T cells promote the pathology of dystrophin-deficient muscle. Clin. Immunol. 98, 235–243. 10.1006/clim.2000.496610.1006/clim.2000.496611161980Spencer M. J., Walsh C. M., Dorshkind K. A., Rodriguez E. M., Tidball J. G. (1997). Myonuclear apoptosis in dystrophic mdx muscle occurs by perforin-mediated cytotoxicity. J. Clin. Investigation 99, 2745–2751. 10.1172/JCI11946410.1172/JCI119464PMC5081219169505Spinazzola J. M., Kunkel L. M. (2016). Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy. Expert Opin. Orphan Drugs 4, 1179–1194. 10.1080/21678707.2016.124061310.1080/21678707.2016.1240613PMC548700728670506Spurney C. F. (2011a). Cardiomyopathy of duchenne muscular dystrophy: Current understanding and future directions. Muscle Nerve 44, 8–19. 10.1002/mus.2209710.1002/mus.2209721674516Spurney C. F., Guerron A. D., Yu Q., Sali A., van der Meulen J. H., Hoffman E. P., et al. (2011b). Membrane sealant Poloxamer P188 protects against isoproterenol induced cardiomyopathy in dystrophin deficient mice. BMC Cardiovasc Disord. 11, 20. 10.1186/1471-2261-11-2010.1186/1471-2261-11-20PMC312364921575230Stedman H. H., Sweeney H. L., Shrager J. B., Maguire H. C., Panettieri R. A., Petrof B., et al. (1991). The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature 352, 536–539. 10.1038/352536a010.1038/352536a01865908Stephenson A. A., Flanigan K. M. (2021). Gene editing and modulation for Duchenne muscular dystrophy. Prog. Mol. Biol. Transl. Sci. 182, 225–255. 10.1016/bs.pmbts.2021.01.02910.1016/bs.pmbts.2021.01.02934175043Straub V., Bittner R. E., Leger J. J., Voit T. (1992). Direct visualization of the dystrophin network on skeletal muscle fiber membrane. J. Cell Biol. 119, 1183–1191. 10.1083/jcb.119.5.118310.1083/jcb.119.5.1183PMC22897251447296 Straub V., Rafael J. A., Chamberlain J. S., Campbell K. P. (1997). Animal models for muscular dystrophy show different patterns of sarcolemmal disruption. Available at: http://www.jcb.org .PMC21397919334342 Suzuki K., Tsunekawa Y., Hernandez-Benitez R., Wu J., Zhu J., Kim E. J., et al. (2016). In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature 540, 144–149. 10.1038/nature20565 10.1038/nature20565PMC533178527851729 Szabo P. L., Ebner J., Koenig X., Hamza O., Watzinger S., Trojanek S., et al. (2021). Cardiovascular phenotype of the Dmd mdx rat - a suitable animal model for Duchenne muscular dystrophy. Dis. Model Mech. 14, dmm047704. 10.1242/dmm.047704 10.1242/dmm.047704PMC792765333619211Tabebordbar M., Lagerborg K. A., Stanton A., King E. M., Ye S., Tellez L., et al. (2021). Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Cell 184, 4919–4938 e22. 10.1016/j.cell.2021.08.02810.1016/j.cell.2021.08.028PMC934497534506722 Tabebordbar M., Zhu K., Cheng J. K. W., Chew W. L., Widrick J. J., Yan W. X., et al. (2016). In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351, 407–411. 10.1126/science.aad5177 10.1126/science.aad5177PMC492447726721686Taglia A., Petillo R., D’Ambrosio P., Picillo E., Torella A., Orsini C., et al. (2015). Clinical features of patients with dystrophinopathy sharing the 45-55 exon deletion of DMD gene. Acta Myol. 34, 9–13.PMC447877226155064Takeda S., Clemens P. R., Hoffman E. P. (2021). Exon-skipping in duchenne muscular dystrophy. J. Neuromuscul. Dis. 8, S343–S358. 10.3233/JND-21068210.3233/JND-210682PMC867353434180420Taylor M., Jefferies J., Byrne B., Lima J., Ambale-Venkatesh B., Ostovaneh M. R., et al. (2019). Cardiac and skeletal muscle effects in the randomized HOPE-Duchenne trial. Neurology 92, e866–e878. 10.1212/WNL.000000000000695010.1212/WNL.0000000000006950PMC639696830674601Terrill J. R., Duong M. N., Turner R., Le Guiner C., Boyatzis A., Kettle A. J., et al. (2016). Levels of inflammation and oxidative stress, and a role for taurine in dystropathology of the Golden Retriever Muscular Dystrophy dog model for Duchenne Muscular Dystrophy. Redox Biol. 9, 276–286. 10.1016/j.redox.2016.08.01610.1016/j.redox.2016.08.016PMC501808227611888Terrill J. R., Radley-Crabb H. G., Grounds M. D., Arthur P. G. (2012). N-Acetylcysteine treatment of dystrophic mdx mice results in protein thiol modifications and inhibition of exercise induced myofibre necrosis. Neuromuscul. Disord. 22, 427–434. 10.1016/j.nmd.2011.11.00710.1016/j.nmd.2011.11.00722206641Terrill J. R., Radley-Crabb H. G., Iwasaki T., Lemckert F. A., Arthur P. G., Grounds M. D. (2013). Oxidative stress and pathology in muscular dystrophies: Focus on protein thiol oxidation and dysferlinopathies. FEBS J. 280, 4149–4164. 10.1111/febs.1214210.1111/febs.1214223332128Tidball J. G., Villalta S. A. (2010). Regulatory interactions between muscle and the immune system during muscle regeneration. Am. J. Physiology-Regulatory, Integr. Comp. Physiology 298, R1173–R1187. 10.1152/ajpregu.00735.200910.1152/ajpregu.00735.2009PMC286752020219869Tidball J. G., Welc S. S., Wehling‐Henricks M. (2018). “Immunobiology of inherited muscular dystrophies,” in Comprehensive physiology (Wiley; ), 1313–1356. 10.1002/cphy.c17005210.1002/cphy.c170052PMC776941830215857Tinsley J., Deconinck N., Fisher R., Kahn D., Phelps S., Gillis J. M., et al. (1998). Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nat. Med. 4, 1441–1444. 10.1038/403310.1038/40339846586Tobin J. F., Celeste A. J. (2005). Myostatin, a negative regulator of muscle mass: Implications for muscle degenerative diseases. Curr. Opin. Pharmacol. 5, 328–332. 10.1016/j.coph.2005.01.01110.1016/j.coph.2005.01.01115907921Townsend D., Blankinship M. J., Allen J. M., Gregorevic P., Chamberlain J. S., Metzger J. M. (2007). Systemic administration of micro-dystrophin restores cardiac geometry and prevents dobutamine-induced cardiac pump failure. Mol. Ther. 15, 1086–1092. 10.1038/sj.mt.630014410.1038/sj.mt.630014417440445Townsend D., Turner I., Yasuda S., Martindale J., Davis J., Shillingford M., et al. (2010). Chronic administration of membrane sealant prevents severe cardiac injury and ventricular dilatation in dystrophic dogs. J. Clin. Investigation 120, 1140–1150. 10.1172/JCI4132910.1172/JCI41329PMC284606020234088Townsend D. W., Yasuda S., McNally E., Metzger J. M. (2011). Distinct pathophysiological mechanisms of cardiomyopathy in hearts lacking dystrophin or the sarcoglycan complex. FASEB J. 25, 3106–3114. 10.1096/fj.10-17891310.1096/fj.10-178913PMC315769021665956Townsend D., Yasuda S., Chamberlain J., Metzger J. M. (2009). Cardiac consequences to skeletal muscle-centric therapeutics for Duchenne muscular dystrophy. Trends Cardiovasc Med. 19, 50–55. 10.1016/j.tcm.2009.04.00610.1016/j.tcm.2009.04.00619577712Townsend D., Yasuda S., Li S., Chamberlain J. S., Metzger J. M. (2008). Emergent dilated cardiomyopathy caused by targeted repair of dystrophic skeletal muscle. Mol. Ther. 16, 832–835. 10.1038/mt.2008.5210.1038/mt.2008.52PMC259284618414480Tsuda T. (2018). Clinical manifestations and overall management strategies for duchenne muscular dystrophy. Methods Mol. Biol. 1687, 19–28. 10.1007/978-1-4939-7374-3_210.1007/978-1-4939-7374-3_229067653Tulangekar A., Sztal T. E. (2021). Inflammation in duchenne muscular dystrophy-exploring the role of neutrophils in muscle damage and regeneration. Biomedicines 9, 1366. 10.3390/biomedicines910136610.3390/biomedicines9101366PMC853359634680483Turner P. R., Westwood T., Regen C. M., Steinhardt R. A. (1988). Increased protein degradation results from elevated free calcium levels found in muscle from mdx mice. Nature 335, 735–738. 10.1038/335735a010.1038/335735a03173492Tyler K. L. (2003). Origins and early descriptions of Duchenne muscular dystrophy. Muscle Nerve 28, 402–422. 10.1002/mus.1043510.1002/mus.1043514506712Van Deutekom J. C. T., Bremmer-Bout M., Janson A. A. M., Ginjaar I. B., Baas F., Den Dunnen J. T., et al. (2001). Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells. Hum. Mol. Genet. 10, 1547–1554. 10.1093/hmg/10.15.154710.1093/hmg/10.15.154711468272Verma A. (2018). Recent advances in antisense oligonucleotide therapy in genetic neuromuscular diseases. Ann. Indian Acad. Neurol. 21, 3–8. 10.4103/aian.AIAN_298_1710.4103/aian.AIAN_298_17PMC590914329720791Vidal B., Serrano A. L., Tjwa M., Suelves M., Ardite E., de Mori R., et al. (2008). Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathway. Genes Dev. 22, 1747–1752. 10.1101/gad.46590810.1101/gad.465908PMC249266118593877Villalta S. A., Rosenberg A. S., Bluestone J. A. (2015). The immune system in Duchenne muscular dystrophy: Friend or foe. Rare Dis. 3, e1010966. 10.1080/21675511.2015.101096610.1080/21675511.2015.1010966PMC458815526481612Voisin V., Se C., Yu H., Gillet B., J M. I., De S., et al. (2005). L -arginine improves dystrophic phenotype in mdx mice. Neurobiol. Dis. 20, 123–130. 10.1016/j.nbd.2005.02.01010.1016/j.nbd.2005.02.01016137573Vulin A., Leturcq F., Kaplan J. (2004). Splicingexonskippingcorrextion-Mice 306, 4.Wagner K. R., Fleckenstein J. L., Amato A. A., Barohn R. J., Bushby K., Escolar D. M., et al. (2008). A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy, 561–571. 10.1002/ana.2133810.1002/ana.2133818335515Wagner K. R., Hamed S., Hadley D. W., Gropman A. L., Burstein A. H., Escolar D. M., et al. (2001). Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Ann. Neurol. 49, 706–711. 10.1002/ana.102310.1002/ana.102311409421Wallace G. Q., Lapidos K. A., Kenik J. S., McNally E. M. (2008). Long-term survival of transplanted stem cells in immunocompetent mice with muscular dystrophy. Am. J. Pathology 173, 792–802. 10.2353/ajpath.2008.08025910.2353/ajpath.2008.080259PMC252707618711004Walsh F. S., Celeste A. J. (2005). Myostatin: A modulator of skeletal-muscle stem cells, 1513–1517.16246158Wang B., Li J., Xiao X. (2000). Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc. Natl. Acad. Sci. U. S. A. 97, 13714–13719. 10.1073/pnas.24033529710.1073/pnas.240335297PMC1764111095710Wang D., Zhong L., Nahid M. A., Gao G. (2014). The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin. Drug Deliv. 11, 345–364. 10.1517/17425247.2014.87125810.1517/17425247.2014.871258PMC409864624386892Wang J. Z., Wu P., Shi Z. M., Xu Y. L., Liu Z. J. (2017). The AAV-mediated and RNA-guided CRISPR/Cas9 system for gene therapy of DMD and BMD. Brain Dev. 39, 547–556. 10.1016/j.braindev.2017.03.02410.1016/j.braindev.2017.03.02428390761Wang Z., Storb R., Halbert C. L., Banks G. B., Butts T. M., Finn E. E., et al. (2012). Successful regional delivery and long-term expression of a dystrophin gene in canine muscular dystrophy: A preclinical model for human therapies. Mol. Ther. 20, 1501–1507. 10.1038/mt.2012.11110.1038/mt.2012.111PMC341249222692496Wang Z., Zhu T., Qiao C., Zhou L., Wang B., Zhang J., et al. (2005). Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat. Biotechnol. 23, 321–328. 10.1038/nbt107310.1038/nbt107315735640Wasala L. P., Watkins T., Wasala N., Burke M., Yue Y., Lai Y., et al. (2022). The implication of hinge 1 and hinge 4 in micro-dystrophin gene therapy for Duchenne muscular dystrophy. Hum. Gene Ther. 34, 459–470. 10.1089/hum.2022.18010.1089/hum.2022.180PMC1021023036310439Watchko J., O’Day T., Wang B., Zhou L., Tang Y., Li J., et al. (2002). Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. Hum. Gene Ther. 13, 1451–1460. 10.1089/1043034026018508510.1089/1043034026018508512215266Wehling M., Spencer M. J., Tidball J. G. (2001). A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice. J. Cell Biol. 155, 123–131. 10.1083/jcb.20010511010.1083/jcb.200105110PMC215080011581289Wei T., Cheng Q., Min Y. L., Olson E. N., Siegwart D. J. (2020). Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing. Nat. Commun. 11, 3232. 10.1038/s41467-020-17029-310.1038/s41467-020-17029-3PMC732015732591530Weir A. P., Burton E. A., Harrod G., Davies K. E. (2002). A- and B-utrophin have different expression patterns and are differentially up-regulated in mdx muscle. J. Biol. Chem. 277, 45285–45290. 10.1074/jbc.M20517720010.1074/jbc.M20517720012235137Weir A. P., Morgan J. E., Davies K. E. (2004). A-utrophin up-regulation in mdx skeletal muscle is independent of regeneration. Neuromuscul. Disord. 14, 19–23. 10.1016/j.nmd.2003.09.00410.1016/j.nmd.2003.09.00414659408Welch E. M., Barton E. R., Zhuo J., Tomizawa Y., Friesen W. J., Trifillis P., et al. (2007). PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 87–91. 10.1038/nature0575610.1038/nature0575617450125Whitehead N. P., Kim M. J., Bible K. L., Adams M. E., Froehner S. C. (2015). A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy. Proc. Natl. Acad. Sci. U. S. A. 112, 12864–12869. 10.1073/pnas.150953611210.1073/pnas.1509536112PMC461160126417069Whitehead N. P., Pham C., Gervasio O. L., Allen D. G. (2008). N-Acetylcysteine ameliorates skeletal muscle pathophysiology in mdx mice. J. Physiol. 586, 2003–2014. 10.1113/jphysiol.2007.14833810.1113/jphysiol.2007.148338PMC237571718258657Whitehead N. P., Yeung E. W., Froehner S. C., Allen D. G. (2010). Skeletal muscle NADPH oxidase is increased and triggers stretch-induced damage in the mdx mouse. PLoS One 5, e15354. 10.1371/journal.pone.001535410.1371/journal.pone.0015354PMC300486421187957Williams I. A., Allen D. G. (2007). The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice. Am. J. Physiol. Heart Circ. Physiol. 293, H1969–H1977. 10.1152/ajpheart.00489.200710.1152/ajpheart.00489.200717573457Wojtal D., Kemaladewi D. U., Malam Z., Abdullah S., Wong T. W., Hyatt E., et al. (2016). Spell checking nature: Versatility of CRISPR/Cas9 for developing treatments for inherited disorders. Am. J. Hum. Genet. 98, 90–101. 10.1016/j.ajhg.2015.11.01210.1016/j.ajhg.2015.11.012PMC471666926686765Wu B., Li Y., Morcos P. A., Doran T. J., Lu P., Lu Q. L. (2009). Octa-guanidine morpholino restores dystrophin expression in cardiac and skeletal muscles and ameliorates pathology in dystrophic mdx mice. Mol. Ther. 17, 864–871. 10.1038/mt.2009.3810.1038/mt.2009.38PMC283513919277018Wu B., Lu P., Benrashid E., Malik S., Ashar J., Doran T. J., et al. (2010). Dose-dependent restoration of dystrophin expression in cardiac muscle of dystrophic mice by systemically delivered morpholino. Gene Ther. 17, 132–140. 10.1038/gt.2009.12010.1038/gt.2009.12019759562Wu B., Moulton H. M., Iversen P. L., Jiang J., Li J., Li J., et al. (2008). Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer. Proc. Natl. Acad. Sci. U. S. A. 105, 14814–14819. 10.1073/pnas.080567610510.1073/pnas.0805676105PMC254644118806224Xiao X. A., Li J. A., Samulski R. J. (1996). Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J. Virol. 70, 8098–8108. 10.1128/Jvi.70.11.8098-8108.199610.1128/Jvi.70.11.8098-8108.1996PMC1908848892935Xu L., Park K. H., Zhao L., Xu J., El Refaey M., Gao Y., et al. (2016). CRISPR-Mediated genome editing restores dystrophin expression and function in mdx mice. Mol. Ther. 24, 564–569. 10.1038/mt.2015.19210.1038/mt.2015.192PMC478691226449883Yang J., Ratovitski T., Brady J. P., Solomon M. B., Wells K. D., Wall R. J. (2001). Expression of myostatin pro domain results in muscular transgenic mice, 361.11599046Yang Y., Wang L., Bell P., McMenamin D., He Z., White J., et al. (2016). A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat. Biotechnol. 34, 334–338. 10.1038/nbt.346910.1038/nbt.3469PMC478648926829317Yasuda S., Townsend D., Michele D. E., Favre E. G., Day S. M., Metzger J. M. (2005). Dystrophic heart failure blocked by membrane sealant poloxamer. Nature 436, 1025–1029. 10.1038/nature0384410.1038/nature0384416025101Yin H., Saleh A. F., Betts C., Camelliti P., Seow Y., Ashraf S., et al. (2011). Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice. Mol. Ther. 19, 1295–1303. 10.1038/mt.2011.7910.1038/mt.2011.79PMC312882321505427Yokota T., Lu Q. L., Partridge T., Kobayashi M., Nakamura A., Takeda S., et al. (2009). Efficacy of systemic morpholino exon-skipping in Duchenne dystrophy dogs. Ann. Neurol. 65, 667–676. 10.1002/ana.2162710.1002/ana.21627PMC595130219288467Young C. S., Hicks M. R., Ermolova N. V., Nakano H., Jan M., Younesi S., et al. (2016). A single CRISPR-cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hiPSC-derived muscle cells. Cell Stem Cell 18, 533–540. 10.1016/j.stem.2016.01.02110.1016/j.stem.2016.01.021PMC482628626877224Young C. S., Mokhonova E., Quinonez M., Pyle A. D., Spencer M. J. (2017). Creation of a novel humanized dystrophic mouse model of duchenne muscular dystrophy and application of a CRISPR/Cas9 gene editing therapy. J. Neuromuscul. Dis. 4, 139–145. 10.3233/JND-17021810.3233/JND-170218PMC556577128505980Yu H. K., Liu X., Pan M., Chen J. W., Liu C., Wu Y., et al. (2022). Performance of passive muscle stiffness in diagnosis and assessment of disease progression in duchenne muscular dystrophy. Ultrasound Med. Biol. 48, 414–421. 10.1016/j.ultrasmedbio.2021.09.00310.1016/j.ultrasmedbio.2021.09.00334893358Yuan J., Ma Y., Huang T., Chen Y., Peng Y., Li B., et al. (2018). Genetic modulation of RNA splicing with a CRISPR-guided cytidine deaminase. Mol. Cell 72, 380–394. 10.1016/j.molcel.2018.09.00210.1016/j.molcel.2018.09.00230293782 Yuasa K., Miyagoe Y., Yamamoto K., Nabeshima Y., Dickson G., Takeda S. (1998). Effective restoration of dystrophin-associated proteins in vivo by adenovirus-mediated transfer of truncated dystrophin cDNAs. FEBS Lett. 425, 329–336. 10.1016/s0014-5793(98)00251-8 10.1016/s0014-5793(98)00251-89559674Yue Y., Ghosh A., Long C., Bostick B., Smith B. F., Kornegay J. N., et al. (2008). A single intravenous injection of adeno-associated virus serotype-9 leads to whole body skeletal muscle transduction in dogs. Mol. Ther. 16, 1944–1952. 10.1038/mt.2008.20710.1038/mt.2008.207PMC270382018827804Zhang Y., Long C., Li H., McAnally J. R., Baskin K. K., Shelton J. M., et al. (2017). CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Sci. Adv. 3, e1602814. 10.1126/sciadv.160281410.1126/sciadv.1602814PMC538974528439558Zhang Y., Nishiyama T., Olson E. N., Bassel-Duby R. (2021). CRISPR/Cas correction of muscular dystrophies. Exp. Cell Res. 408, 112844. 10.1016/j.yexcr.2021.11284410.1016/j.yexcr.2021.112844PMC853095934571006Zhao Q. D., Viswanadhapalli S., Williams P., Shi Q., Tan C., Yi X., et al. (2015). NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways. Circulation 131, 643–655. 10.1161/CIRCULATIONAHA.114.01107910.1161/CIRCULATIONAHA.114.011079PMC456875625589557Zhou L., Porter J. D., Cheng G., Gong B., Hatala D. A., Merriam A. P., et al. (2006). Temporal and spatial mRNA expression patterns of TGF-beta1, 2, 3 and TbetaRI, II, III in skeletal muscles of mdx mice. Neuromuscul. Disord. 16, 32–38. 10.1016/j.nmd.2005.09.00910.1016/j.nmd.2005.09.00916373085Zhu P., Wu F., Mosenson J., Zhang H., He T. C., Wu W. S. (2017). CRISPR/Cas9-Mediated genome editing corrects dystrophin mutation in skeletal muscle stem cells in a mouse model of muscle dystrophy. Mol. Ther. Nucleic Acids 7, 31–41. 10.1016/j.omtn.2017.02.00710.1016/j.omtn.2017.02.007PMC536368228624206Zhu X., Hadhazy M., Wehling M., Tidball J. G. (2000). Dominant negative myostatin produces hypertrophy without hyperplasia in muscle. FEBS Lett. 474, 71–75. 10.1016/s0014-5793(00)01570-210.1016/s0014-5793(00)01570-210828454Zincarelli C., Soltys S., Rengo G., Rabinowitz J. E. (2008). Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection. Mol. Ther. 16, 1073–1080. 10.1038/mt.2008.7610.1038/mt.2008.7618414476 Zuris J. A., Thompson D. B., Shu Y., Guilinger J. P., Bessen J. L., Hu J. H., et al. (2015). Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo . Nat. Biotechnol. 33, 73–80. 10.1038/nbt.3081 10.1038/nbt.3081PMC428940925357182Wagner K. R., Kuntz N. L., Koenig E., East L., Upadhyay S., Shieh P. B. (2021). Safety, tolerability, and pharmacokinetics of casimersen in patients with Duchenne muscular dystrophy amenable to exon dose-titration trial. Muscle Nerve. 64, 285–292. 10.1002/mus.2734710.1002/mus.27347PMC929099334105177