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Therapeutic approaches for Duchenne muscular dystrophy

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From Nature Reviews Drug Discovery

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Abstract

Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disorder and a priority candidate for molecular and cellular therapeutics. Although rare, it is the most common inherited myopathy affecting children and so has been the focus of intense research activity. It is caused by mutations that disrupt production of the dystrophin protein, and a plethora of drug development approaches are under way that aim to restore dystrophin function, including exon skipping, stop codon readthrough, gene replacement, cell therapy and gene editing. These efforts have led to the clinical approval of four exon skipping antisense oligonucleotides, one stop codon readthrough drug and one gene therapy product, with other approvals likely soon. Here, we discuss the latest therapeutic strategies that are under development and being deployed to treat DMD. Lessons from these drug development programmes are likely to have a major impact on the DMD field, but also on molecular and cellular medicine more generally. Thus, DMD is a pioneer disease at the forefront of future drug discovery efforts, with these experimental treatments paving the way for therapies using similar mechanisms of action being developed for other genetic diseases.

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Fig. 1: The dystrophin gene and protein.
Fig. 2: Restoration of dystrophin expression by exon skipping.
Fig. 3: Antisense oligonucleotide therapies for Duchenne muscular dystrophy.
Fig. 4: Restoration of dystrophin by stop codon readthrough therapy.
Fig. 5: Micro-dystrophin gene replacement therapy.

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References

  1. Hoffman, E. P., Brown, R. H. & Kunkel, L. M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, 919–928 (1987).

    Article  CAS  PubMed  Google Scholar 

  2. Moriuchi, T., Kagawa, N., Mukoyama, M. & Hizawa, K. Autopsy analyses of the muscular dystrophies. Tokushima J. Exp. Med. 40, 83–93 (1993).

    CAS  PubMed  Google Scholar 

  3. Chiang, D. Y. et al. Relation of cardiac dysfunction to rhythm abnormalities in patients with Duchenne or Becker muscular dystrophies. Am. J. Cardiol. 117, 1349–1354 (2016).

    Article  PubMed  Google Scholar 

  4. Ishikawa, Y. et al. Duchenne muscular dystrophy: survival by cardio-respiratory interventions. Neuromuscul. Disord. 21, 47–51 (2011).

    Article  PubMed  Google Scholar 

  5. Duan, D., Goemans, N., Takeda, S., Mercuri,E. & Aartsma-Rus, A. Duchenne muscular dystrophy Nat. Rev. Dis. Prim. 7, 14 (2021).

    Article  Google Scholar 

  6. Petrof, B. J., Shrager, J. B., Stedman, H. H., Kelly, A. M. & Sweeney, H. L. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc. Natl Acad. Sci. USA 90, 3710–3714 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ricotti, V. et al. Long-term benefits and adverse effects of intermittent versus daily glucocorticoids in boys with Duchenne muscular dystrophy. J. Neurol. Neurosurg. Psychiatry 84, 698–705 (2013).

    Article  PubMed  Google Scholar 

  8. Birnkrant, D. J. et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol. 17, 347–361 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kourakis, S. et al. Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: can we do better? Orphanet J. Rare Dis. 16, 117 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Vestergaard, P. et al. Fracture risk in patients with muscular dystrophy and spinal muscular atrophy. J. Rehabil. Med. 33, 150–155 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Hoffman, E. P. et al. Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function. Neurology 93, e1312–e1323 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ervasti, J. M. & Campbell, K. P. Membrane organization of the dystrophin-glycoprotein complex. Cell 66, 1121–1131 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Rybakova, I. N., Patel, J. R. & Ervasti, J. M. The dystrophin complex forms a mechanically strong link between the sarcolemma and costameric actin. J. Cell Biol. 150, 1209–1214 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Spence, H. J., Dhillon, A. S., James, M. & Winder, S. J. Dystroglycan, a scaffold for the ERK-MAP kinase cascade. EMBO Rep. 5, 484–489 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dumont, N. A. et al. Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. Nat. Med. 21, 1455–1463 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Roberts, T. C. et al. Multi-level omics analysis in a murine model of dystrophin loss and therapeutic restoration. Hum. Mol. Genet. 24, 6756–6768 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. van Westering, T. L. E. et al. Mutation-independent proteomic signatures of pathological progression in murine models of duchenne muscular dystrophy. Mol. Cell Proteom. 19, 2047–2067 (2020).

    Article  Google Scholar 

  18. Sandonà, D. & Betto, R. Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects. Expert. Rev. Mol. Med. 11, e28 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Consalvi, S. et al. Histone deacetylase inhibitors in the treatment of muscular dystrophies: epigenetic drugs for genetic diseases. Mol. Med. 17, 457–465 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boldrin, L., Zammit, P. S. & Morgan, J. E. Satellite cells from dystrophic muscle retain regenerative capacity. Stem Cell Res. 14, 20–29 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Meng, J., Bencze, M., Asfahani, R., Muntoni, F. & Morgan, J. E. The effect of the muscle environment on the regenerative capacity of human skeletal muscle stem cells. Skelet. Muscle 5, 11 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wang, Y. et al. Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nat. Genet. 46, 601–606 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gallia, G. L. et al. Genomic analysis identifies frequent deletions of dystrophin in olfactory neuroblastoma. Nat. Commun. 9, 5410 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bladen, C. L. et al. The TREAT-NMD DMD global database: analysis of more than 7,000 duchenne muscular dystrophy mutations. Hum. Mutat. 36, 395–402 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. White, S. J. et al. Duplications in the DMD gene. Hum. Mutat. 27, 938–945 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Nakamura, A. et al. Deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy. J. Hum. Genet. 61, 663–667 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Nakamura, A. et al. Comparison of the phenotypes of patients harboring in-frame deletions starting at exon 45 in the Duchenne muscular dystrophy gene indicates potential for the development of exon skipping therapy. J. Hum. Genet. 62, 459–463 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Muntoni, F., Torelli, S. & Ferlini, A. Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol. 2, 731–740 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. England, S. B. et al. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 343, 180–182 (1990).

    Article  CAS  PubMed  Google Scholar 

  30. Matsumura, K. et al. Immunohistochemical analysis of dystrophin-associated proteins in Becker/Duchenne muscular dystrophy with huge in-frame deletions in the NH2-terminal and rod domains of dystrophin. J. Clin. Invest. 93, 99–105 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Monaco, A. P., Bertelson, C. J., Liechti-Gallati, S., Moser, H. & Kunkel, L. M. An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 2, 90–95 (1988).

    Article  CAS  PubMed  Google Scholar 

  32. Anwar, S., He, M., Lim, K. R. Q., Maruyama, R. & Yokota, T. A genotype-phenotype correlation study of exon skip-equivalent in-frame deletions and exon skip-amenable out-of-frame deletions across the DMD gene to simulate the effects of exon-skipping therapies: a meta-analysis. J. Pers. Med. 11, 46 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Koenig, M. et al. The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am. J. Hum. Genet. 45, 498–506 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Malhotra, S. et al. Frame-shift deletions in patients with Duchenne and Becker muscular dystrophy. Science 242, 755–759 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Del Rio-Pertuz, G., Morataya, C., Parmar, K., Dubay, S. & Argueta-Sosa, E. Dilated cardiomyopathy as the initial presentation of Becker muscular dystrophy: a systematic review of published cases. Orphanet J. Rare Dis. 17, 194 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Aartsma-Rus, A. et al. Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum. Mutat. 30, 293–299 (2009).

    Article  PubMed  Google Scholar 

  37. Syed, Y. Y. Eteplirsen: first global approval. Drugs 76, 1699–1704 (2016).

    Article  CAS  PubMed  Google Scholar 

  38. Heo, Y.-A. Golodirsen: first approval. Drugs 80, 329–333 (2020).

    Article  PubMed  Google Scholar 

  39. Shirley, M. Casimersen: first approval. Drugs 81, 875–879 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Komaki, H. et al. Systemic administration of the antisense oligonucleotide NS-065/NCNP-01 for skipping of exon 53 in patients with Duchenne muscular dystrophy. Sci. Transl. Med. 10, eaan0713 (2018).

    Article  PubMed  Google Scholar 

  41. Clemens, P. R. et al. 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 (2020).

    Article  PubMed  Google Scholar 

  42. Dhillon, S. Viltolarsen: first approval. Drugs 80, 1027–1031 (2020).

    Article  CAS  PubMed  Google Scholar 

  43. Aartsma-Rus, A. & Goemans, N. A sequel to the eteplirsen saga: eteplirsen is approved in the United States but was not approved in Europe. Nucleic Acid. Ther. 29, 13–15 (2018).

    Article  PubMed  Google Scholar 

  44. Muntoni, F., Fletcher, S. & Wilton, S. Response to “Railroading at the FDA”. Nat. Biotechnol. 35, 207–209 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Aartsma-Rus, A. & Krieg, A. M. FDA approves eteplirsen for Duchenne muscular dystrophy: the next chapter in the eteplirsen saga. Nucleic Acid. Ther. 27, 1–3 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dowling, J. J. Eteplirsen therapy for Duchenne muscular dystrophy: skipping to the front of the line. Nat. Rev. Neurol. 12, 675–676 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. FDA Briefing Document, Peripheral and Central Nervous System Drugs Advisory Committee Meeting, 22 January 2016, NDA 206488, Eteplirsen (FDA, 2016); https://www.fda.gov/files/advisory%20committees/published/FDA-Briefing-Information-for-the-January-22-2016-Meeting-of-the-Peripheral-and-Central-Nervous-System-Drugs-Advisory-Committee.pdf.

  48. No authors listed. Railroading at the FDA. Nat. Biotechnol. 34, 1078–1078 (2016).

    Article  Google Scholar 

  49. Charleston, J. S. et al. Eteplirsen treatment for Duchenne muscular dystrophy: exon skipping and dystrophin production. Neurology 90, e2146–e2154 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Servais, L. et al. Long-term safety and efficacy data of golodirsen in ambulatory patients with Duchenne muscular dystrophy amenable to exon 53 skipping: a first-in-human, multicenter, two-part, open-label, phase 1/2 trial. Nucleic Acid. Ther. 32, 29–39 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mendell, J. R. et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann. Neurol. 74, 637–647 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Mendell, J. R. et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann. Neurol. 79, 257–271 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wu, B. et al. Dose-dependent restoration of dystrophin expression in cardiac muscle of dystrophic mice by systemically delivered morpholino. Gene Ther. 17, 132–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Mendell, J. R. et al. Comparison of long-term ambulatory function in patients with Duchenne muscular dystrophy treated with eteplirsen and matched natural history controls. J. Neuromuscul. Dis. 8, 469–479 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Roberts, T. C., Langer, R. Wood, M. J. A. Advances in oligonucleotide drug delivery Nat. Rev. Drug Discov. 19, 673–694 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Betts, C. et al. Pip6-PMO, a new generation of peptide-oligonucleotide conjugates with improved cardiac exon skipping activity for DMD treatment. Mol. Ther. Nucleic Acids 1, e38 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Betts, C. A. et al. Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice. Sci. Rep. 5, 8986 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sarepta therapeutics reports positive clinical results from phase 2 MOMENTUM study of SRP-5051 in patients with duchenne muscular dystrophy amenable to skipping exon 51. Sarepta Therapeutics (5 May 2021); https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-reports-positive-clinical-results-phase-2.

  59. Moulton, H. M. & Moulton, J. D. Morpholinos and their peptide conjugates: therapeutic promise and challenge for Duchenne muscular dystrophy. Biochim. Biophys. Acta 1798, 2296–2303 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Amantana, A. et al. Pharmacokinetics, biodistribution, stability and toxicity of a cell-penetrating peptide-morpholino oligomer conjugate. Bioconjug. Chem. 18, 1325–1331 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. PepGen reports positive data from phase 1 trial of PGN-EDO51 for the treatment of Duchenne muscular dystrophy. PepGen (28 September 2022); https://investors.pepgen.com/news-releases/news-release-details/pepgen-reports-positive-data-phase-1-trial-pgn-edo51-treatment/.

  62. Kreher, N. et al. P.194 Development of a novel, EEV-conjugated PMO for Duchenne muscular dystrophy. Neuromuscul. Disord. 32, S126 (2022).

    Article  Google Scholar 

  63. Avidity Biosciences Announces Phase 1/2 EXPLORE44TM Trial of AOC 1044 for Duchenne Muscular Dystrophy Mutations Amenable to Exon 44 Skipping (Avidity Biosciences, 2022); https://aviditybiosciences.investorroom.com/2022-10-11-Avidity-Biosciences-Announces-Phase-1-2-EXPLORE44-TM-Trial-of-AOC-1044-for-Duchenne-Muscular-Dystrophy-Mutations-Amenable-to-Exon-44-Skipping.

  64. Desjardins, C. A. et al. Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice. Nucleic Acids Res. 50, 11401–11414 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Aoki, Y. et al. Bodywide skipping of exons 45–55 in dystrophic mdx52 mice by systemic antisense delivery. Proc. Natl Acad. Sci. USA 109, 13763–13768 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Béroud, C. et al. Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Hum. Mutat. 28, 196–202 (2007).

    Article  PubMed  Google Scholar 

  67. Wave Life Sciences provides positive update on proof-of-concept study for WVE-N531 in Duchenne muscular dystrophy. GlobeNewswire News Room (WAVE Life Science USA, 2022); https://www.globenewswire.com/news-release/2022/12/19/2576214/0/en/Wave-Life-Sciences-Provides-Positive-Update-on-Proof-of-Concept-Study-for-WVE-N531-in-Duchenne-Muscular-Dystrophy.html.

  68. Kandasamy, P. et al. Control of backbone chemistry and chirality boost oligonucleotide splice switching activity. Nucleic Acids Res. 50, 5443–5466 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Iwamoto, N. et al. Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat. Biotechnol. 35, 845–851 (2017).

    Article  CAS  PubMed  Google Scholar 

  70. Wan, W. B. et al. Synthesis, biophysical properties and biological activity of second generation antisense oligonucleotides containing chiral phosphorothioate linkages. Nucleic Acids Res. 42, 13456–13468 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wave Life Sciences provides update on phase 1b/2a PRECISION-HD trials - Wave Life Sciences. Wave Life Sciences (2021); https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-provides-update-phase-1b2a-precision-hd.

  72. Wave Life Sciences announces discontinuation of suvodirsen development for Duchenne muscular dystrophy. Wave Life Sciences (16 December 2019); https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-discontinuation-suvodirsen.

  73. Ito, K. et al. Renadirsen, a novel 2’OMeRNA/ENA® chimera antisense oligonucleotide, induces robust exon 45 skipping for dystrophin in vivo. Curr. Issues Mol. Biol. 43, 1267–1281 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Goyenvalle, A. et al. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat. Med. 21, 270–275 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Zarrouki, F. et al. Partial restoration of brain dystrophin and behavioral deficits by exon skipping in the muscular dystrophy X-linked (mdx) mouse. Ann. Neurol. 92, 213–229 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. De Angelis, F. G. et al. Chimeric snRNA molecules carrying antisense sequences against the splice junctions of exon 51 of the dystrophin pre-mRNA induce exon skipping and restoration of a dystrophin synthesis in Delta 48-50 DMD cells. Proc. Natl Acad. Sci. USA 99, 9456–9461 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Goyenvalle, A. et al. Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping. Science 306, 1796–1799 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Simmons, T. R. et al. Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skipping. Mol. Ther. Methods Clin. Dev. 21, 325–340 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wein, N. et al. Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nat. Med. 20, 992–1000 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Nationwide Children’s Hospital Announces Restoration of Full-Length Dystrophin Using dup 2 Gene Therapy Approach (Parent Project Muscular Dystrophy, 2022); https://www.parentprojectmd.org/nationwide-childrens-hospital-announces-restoration-of-full-length-dystrophin-using-duplication-2-gene-therapy-approach/.

  81. Barton-Davis, E. R., Cordier, L., Shoturma, D. I., Leland, S. E. & Sweeney, H. L. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J. Clin. Invest. 104, 375–381 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wagner, K. R. et al. Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Ann. Neurol. 49, 706–711 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Politano, L. et al. Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results. Acta Myol. 22, 15–21 (2003).

    CAS  PubMed  Google Scholar 

  84. Malik, V. et al. Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann. Neurol. 67, 771–780 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Hayward, R. S. et al. Adverse effects of a single dose of gentamicin in adults: a systematic review. Br. J. Clin. Pharmacol. 84, 223–238 (2018).

    Article  CAS  PubMed  Google Scholar 

  86. Welch, E. M. et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 87–91 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Ryan, N. J. Ataluren: first global approval. Drugs 74, 1709–1714 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Bushby, K. et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve 50, 477–487 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. McDonald, C. M. et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390, 1489–1498 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. No authors listed.Duchenne drug clings on for FDA nodNat. Biotechnol. 35, 999 (2017).

    Article  Google Scholar 

  91. Campbell, C. et al. Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy. J. Comp. Eff. Res. 9, 973–984 (2020).

    Article  PubMed  Google Scholar 

  92. Auld, D. S. et al. Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124. Proc. Natl Acad. Sci. USA 107, 4878–4883 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. McElroy, S. P. et al. A lack of premature termination codon read-through efficacy of PTC124 (Ataluren) in a diverse array of reporter assays. PLoS Biol. 11, e1001593 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Halbert, C. L., Rutledge, E. A., Allen, J. M., Russell, D. W. & Miller, A. D. Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes. J. Virol. 74, 1524–1532 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gruntman, A. M. et al. Gene transfer in skeletal and cardiac muscle using recombinant adeno-associated virus. Curr. Protoc. Microbiol. https://doi.org/10.1002/9780471729259.mc14d03s28 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Qiao, C., Koo, T., Li, J., Xiao, X. & Dickson, J. G. Gene therapy in skeletal muscle mediated by adeno-associated virus vectors. Methods Mol. Biol. 807, 119–140 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Gregorevic, P. et al. Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat. Med. 10, 828–834 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Duan, D. Systemic AAV micro-dystrophin gene therapy for duchenne muscular dystrophy. Mol. Ther. 26, 2337–2356 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bourdon, A. et al. Evaluation of the dystrophin carboxy-terminal domain for micro-dystrophin gene therapy in cardiac and skeletal muscles in the DMDmdx rat model. Gene Ther. 29, 520–535 (2022).

    Article  CAS  PubMed  Google Scholar 

  100. Cox, G. A. et al. Overexpression of dystrophin in transgenic mdx mice eliminates dystrophic symptoms without toxicity. Nature 364, 725–729 (1993).

    Article  CAS  PubMed  Google Scholar 

  101. Potter, R. A. et al. Dose-escalation study of systemically delivered rAAVrh74.MHCK7.micro-dystrophin in the mdx mouse model of duchenne muscular dystrophy. Hum. Gene Ther. 32, 375–389 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yue, Y. et al. Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus. Hum. Mol. Genet. 24, 5880–5890 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Le Guiner, C. et al. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Nat. Commun. 8, 16105 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Salva, M. Z. et al. Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Mol. Ther. 15, 320–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Chicoine, L. G. et al. Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin α2 surrogates. Mol. Ther. 22, 713–724 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zygmunt, D. A., Crowe, K. E., Flanigan, K. M. & Martin, P. T. Comparison of serum rAAV serotype-specific antibodies in patients with duchenne muscular dystrophy, becker muscular dystrophy, inclusion body myositis, or GNE myopathy. Hum. Gene Ther. 28, 737–746 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Mendell, J. R. et al. Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in children with duchenne muscular dystrophy: a nonrandomized controlled trial. JAMA Neurol. 77, 1122–1131 (2020).

    Article  PubMed  Google Scholar 

  108. Willcocks, R. J. et al. Assessment of rAAVrh.74.MHCK7.micro-dystrophin gene therapy using magnetic resonance imaging in children with duchenne muscular dystrophy. JAMA Netw. Open 4, e2031851 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Mendell, J. et al. A multicenter randomized, double-blind, placebo-controlled, gene-delivery clinical trial of rAAVrh74.MHCK7.micro-dystrophin for Duchenne muscular dystrophy [Abstr.]. Neurology 96 (Suppl. 15), 4478 (2021).

    Google Scholar 

  110. Sarepta Therapeutics announces top-line results for part 1 of study 102 evaluating SRP-9001, its investigational gene therapy for the treatment of Duchenne muscular dystrophy. Sarepta Therapeutics (7 Junuary 2021); https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-top-line-results-part-1-study-102.

  111. Sarepta Therapeutics’ investigational gene therapy SRP-9001 for Duchenne muscular dystrophy demonstrates significant functional improvements across multiple studies. Sarepta Therapeutics (6 July 2022); https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-investigational-gene-therapy-srp-9001.

  112. Sarepta Therapeutics announces that U.S. FDA has accepted for filing and granted priority review for the Biologics License Application for SRP-9001, Sarepta’s gene therapy for the treatment of ambulant individuals with Duchenne muscular dystrophy. Sarepta Therapeutics (28 November 2022); https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-us-fda-has-accepted-filing-and.

  113. Sarepta Therapeutics announces FDA approval of ELEVIDYS, the first gene therapy to treat Duchenne muscular dystrophy. Sarepta Therapeutics (22 June 2023); https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene.

  114. Philippidis, A. After patient death, FDA places hold on Pfizer Duchenne muscular dystrophy gene therapy trial. Hum. Gene Ther. 33, 111–115 (2022).

    Article  CAS  Google Scholar 

  115. Philippidis, A. Pfizer eyes resuming phase III enrollment, investigates phase Ib death tied to Duchenne muscular dystrophy candidate. Hum. Gene Ther. 33, 215–217 (2022).

    Article  CAS  Google Scholar 

  116. Pfizer’s new phase 1b results of gene therapy in ambulatory boys with Duchenne muscular dystrophy (DMD) support advancement into pivotal phase 3 study. Pfizer (15 May 2020); https://www.pfizer.com/news/press-release/press-release-detail/pfizers-new-phase-1b-results-gene-therapy-ambulatory-boys.

  117. Philippidis, A. FDA lifts clinical hold on Pfizer DMD gene therapy linked to patient death. GEN - Genetic Engineering and Biotechnology News (28 April 2022); https://www.genengnews.com/topics/genome-editing/gene-therapy/fda-lifts-clinical-hold-on-pfizer-dmd-gene-therapy-linked-to-patient-death/.

  118. Pfizer announces amendment to ongoing gene therapy phase III trial. Parent Project Muscular Dystrophy (28 September 2021); https://www.parentprojectmd.org/pfizer-announces-amendment-to-ongoing-gene-therapy-phase-iii-trial/.

  119. Collaborative analysis reveals ‘class effect’ in DMD safety issues. BioSpace (19 May 2022); https://www.biospace.com/article/pfizer-sarepta-genethon-solid-bio-team-up-to-fight-dmd/.

  120. Solid Biosciences provides SGT-001 program update. Solid Biosciences (19 November 2019); https://www.solidbio.com/about/media/press-releases/solid-biosciences-provides-sgt-001-program-update.

  121. Solid Biosciences announces FDA lifts clinical hold on IGNITE DMD clinical trial. Solid Biosciences (1 October 2020); https://www.solidbio.com/about/media/press-releases/solid-biosciences-announces-fda-lifts-clinical-hold-on-ignite-dmd-clinical-trial.

  122. Solid Biosciences reports fourth quarter and full-year 2021 financial results and 2-year efficacy and safety data from the ongoing phase I/II IGNITE DMD clinical trial of SGT-001. Solid Biosciences (14 March 2022); https://www.solidbio.com/about/media/press-releases/solid-biosciences-reports-fourth-quarter-and-full-year-2021-financial-results-and-2-year-efficacy-and-safety-data-from-the-ongoing-phase-i-ii-ignite-dmd-clinical-trial-of-sgt-001.

  123. High-dose AAV gene therapy deaths. Nat. Biotechnol. 38, 910 (2020).

    Article  Google Scholar 

  124. Lysogene confirms child’s death in phase II/III gene therapy trial. GEN (26 October 2020); https://www.genengnews.com/news/lysogene-confirms-childs-death-in-phase-ii-iii-gene-therapy-trial/.

  125. Reuters. Novartis reports Zolgensma caused two deaths from liver failure. Reuters (11 August 2022); https://www.reuters.com/business/healthcare-pharmaceuticals/novartis-reports-zolgensma-caused-two-deaths-liver-failure-2022-08-11/.

  126. Hinderer, C. et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum. Gene Ther. 29, 285–298 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hale, C. Solid Bio Sees Yet Another Clinical Hold for its DMD Gene Therapy (Fierce Biotech, 2019); https://www.fiercebiotech.com/biotech/solid-bio-sees-yet-another-clinical-hold-for-its-dmd-gene-therapy.

  128. Jeune, V. L., Joergensen, J. A., Hajjar, R. J. & Weber, T. Pre-existing anti–adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum. Gene Ther. Methods 24, 59–67 (2013).

    Article  PubMed Central  Google Scholar 

  129. Mendell, J. R. et al. Dystrophin immunity in Duchenne’s muscular dystrophy. N. Engl. J. Med. 363, 1429–1437 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Li, N. et al. The effect of immunomodulatory treatments on anti-Dystrophin immune response after AAV gene therapy in dystrophin deficient mdx mice. J. Neuromuscul. Dis. 8, S325–S340 (2021).

    Article  PubMed  Google Scholar 

  131. Rivera, V. M. et al. Long-term pharmacologically regulated expression of erythropoietin in primates following AAV-mediated gene transfer. Blood 105, 1424–1430 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Penaud-Budloo, M. et al. Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle. J. Virol. 82, 7875–7885 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Le Hir, M. et al. AAV genome loss from dystrophic mouse muscles during AAV-U7 snRNA-mediated exon-skipping therapy. Mol. Ther. 21, 1551–1558 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Das, A. et al. Epigenetic silencing of recombinant adeno-associated virus genomes by NP220 and the HUSH complex. J. Virol. 96, e0203921 (2022).

    Article  PubMed  Google Scholar 

  135. Mollard, A. et al. Muscle regeneration affects adeno associated virus 1 mediated transgene transcription. Sci. Rep. 12, 9674 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Morgan, J. E., Hoffman, E. P. & Partridge, T. A. Normal myogenic cells from newborn mice restore normal histology to degenerating muscles of the mdx mouse. J. Cell Biol. 111, 2437–2449 (1990).

    Article  CAS  PubMed  Google Scholar 

  137. Partridge, T. A., Morgan, J. E., Coulton, G. R., Hoffman, E. P. & Kunkel, L. M. Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature 337, 176–179 (1989).

    Article  CAS  PubMed  Google Scholar 

  138. Garcia, S. M. et al. High-yield purification, preservation, and serial transplantation of human satellite cells. Stem Cell Rep. 10, 1160–1174 (2018).

    Article  CAS  Google Scholar 

  139. Ferrari, G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279, 1528–1530 (1998).

    Article  CAS  PubMed  Google Scholar 

  140. Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Cossu, G. et al. Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy. EMBO Mol. Med. 7, 1513–1528 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Dellavalle, A. et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat. Cell Biol. 9, 255–267 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Torrente, Y. et al. Autologous transplantation of muscle-derived CD133+ stem cells in Duchenne muscle patients. Cell Transpl. 16, 563–577 (2007).

    Article  CAS  Google Scholar 

  144. Young, C. S. et al. 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 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Skuk, D. et al. Dystrophin expression in muscles of duchenne muscular dystrophy patients after high-density injections of normal myogenic cells. J. Neuropathol. Exp. Neurol. 65, 371–386 (2006).

    Article  CAS  PubMed  Google Scholar 

  146. Motohashi, N., Shimizu-Motohashi, Y., Roberts, T. C. & Aoki, Y. Potential therapies using myogenic stem cells combined with bio-engineering approaches for treatment of muscular dystrophies. Cells 8, 1066 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Skuk, D. & Tremblay, J. P. Myoblast transplantation: the current status of a potential therapeutic tool for myopathies. J. Muscle Res. Cell Motil. 24, 285–300 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Taylor, M. et al. Cardiac and skeletal muscle effects in the randomized HOPE-Duchenne trial. Neurology 92, e866–e878 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  149. McDonald, C. M. et al. 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 (2022).

    Article  CAS  PubMed  Google Scholar 

  150. Hanson, B., Wood, M. J. A. & Roberts, T. C. Molecular correction of Duchenne muscular dystrophy by splice modulation and gene editing. RNA Biol. 18, 1048–1062 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819–823 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Tabebordbar, M. et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351, 407–411 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Nelson, C. E. et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351, 403–407 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. Long, C. et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351, 400–403 (2016).

    Article  CAS  PubMed  Google Scholar 

  155. Amoasii, L. et al. Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy. Sci. Transl. Med. 9, eaan8081 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Arnett, A. L. et al. Adeno-associated viral (AAV) vectors do not efficiently target muscle satellite cells. Mol. Ther. Methods Clin. Dev. 1, 14038 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Nance, M. E. et al. AAV9 edits muscle stem cells in normal and dystrophic adult mice. Mol. Ther. 27, 1568–1585 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kwon, J. B. et al. In vivo gene editing of muscle stem cells with adeno-associated viral vectors in a mouse model of Duchenne muscular dystrophy. Mol. Ther. Methods Clin. Dev. 19, 320–329 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ousterout, D. G. et al. Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. Nat. Commun. 6, 6244 (2015).

    Article  CAS  PubMed  Google Scholar 

  160. Liao, H.-K. et al. In vivo target gene activation via CRISPR/Cas9-mediated trans-epigenetic modulation. Cell 171, 1495–1507.e15 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Gilbert, L. A. et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154, 442–451 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. To Our Community: An Update On Our CRD-TMH-001 Clinical Trial (Cure Rare Disease, 2022); https://www.cureraredisease.org/blog-posts/to-our-community-an-update-on-our-crd-tmh-001-clinical-trial.

  163. Lek, A. et al. Unexpected death of a Duchenne muscular dystrophy patient in an N-of-1 Trial of rAAV9-delivered CRISPR-transactivator. Preprint at https://doi.org/10.1101/2023.05.16.23289881 (2023).

  164. Pipeline and Progress (Cure Rare Disease, accessed 2023); https://www.cureraredisease.org/our-approach/pipeline-and-progress#section_1.

  165. Hanson, B. et al. Non-uniform dystrophin re-expression after CRISPR-mediated exon excision in the dystrophin/utrophin double-knockout mouse model of DMD. Mol. Ther. - Nucleic Acids 30, 379–397 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Simhadri, V. L. et al. Prevalence of pre-existing antibodies to CRISPR-associated nuclease Cas9 in the USA population. Mol. Ther. Methods Clin. Dev. 10, 105–112 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Charlesworth, C. T. et al. Identification of preexisting adaptive immunity to Cas9 proteins in humans. Nat. Med. 25, 249–254 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Wagner, D. L. et al. High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population. Nat. Med. 25, 242–248 (2019).

    Article  CAS  PubMed  Google Scholar 

  169. Bengtsson, N. E. et al. Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. Nat. Commun. 8, 14454 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Zhang, Y. et al. CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Sci. Adv. 3, e1602814 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Porto, E. M., Komor, A. C., Slaymaker, I. M. & Yeo, G. W. Base editing: advances and therapeutic opportunities. Nat. Rev. Drug. Discov. 19, 839–859 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Xu, L. et al. Efficient precise in vivo base editing in adult dystrophic mice. Nat. Commun. 12, 3719 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Dianov, G. L. & Hübscher, U. Mammalian base excision repair: the forgotten archangel. Nucleic Acids Res. 41, 3483–3490 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Ryu, S.-M. et al. Adenine base editing in mouse embryos and an adult mouse model of Duchenne muscular dystrophy. Nat. Biotechnol. 36, 536–539 (2018).

    Article  CAS  PubMed  Google Scholar 

  175. Chemello, F. et al. Precise correction of Duchenne muscular dystrophy exon deletion mutations by base and prime editing. Sci. Adv. 7, eabg4910 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149–157 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Blake, D. J., Tinsley, J. M. & Davies, K. E. Utrophin: a structural and functional comparison to dystrophin. Brain Pathol. 6, 37–47 (1996).

    Article  CAS  PubMed  Google Scholar 

  178. Tinsley, J. M. et al. Primary structure of dystrophin-related protein. Nature 360, 591–593 (1992).

    Article  CAS  PubMed  Google Scholar 

  179. Love, D. R. et al. An autosomal transcript in skeletal muscle with homology to dystrophin. Nature 339, 55–58 (1989).

    Article  CAS  PubMed  Google Scholar 

  180. Anthony, K. et al. Biochemical characterization of patients with in-frame or out-of-frame DMD deletions pertinent to exon 44 or 45 skipping. JAMA Neurol. 71, 32–40 (2014).

    Article  PubMed  Google Scholar 

  181. Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, S. D. & Campbell, K. P. Association of dystrophin-related protein with dystrophin-associated proteins in mdx mouse muscle. Nature 360, 588–591 (1992).

    Article  CAS  PubMed  Google Scholar 

  182. Deconinck, A. E. et al. Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 90, 717–727 (1997).

    Article  CAS  PubMed  Google Scholar 

  183. Grady, R. M. et al. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell 90, 729–738 (1997).

    Article  CAS  PubMed  Google Scholar 

  184. Tinsley, J. et al. Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nat. Med. 4, 1441–1444 (1998).

    Article  CAS  PubMed  Google Scholar 

  185. Squire, S. et al. Prevention of pathology in mdx mice by expression of utrophin: analysis using an inducible transgenic expression system. Hum. Mol. Genet. 11, 3333–3344 (2002).

    Article  CAS  PubMed  Google Scholar 

  186. Fisher, R. et al. Non-toxic ubiquitous over-expression of utrophin in the mdx mouse. Neuromuscul. Disord. 11, 713–721 (2001).

    Article  CAS  PubMed  Google Scholar 

  187. Song, Y. et al. Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models. Nat. Med. 25, 1505–1511 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Chancellor, D. R. et al. Discovery of 2-arylbenzoxazoles as upregulators of utrophin production for the treatment of Duchenne muscular dystrophy. J. Med. Chem. 54, 3241–3250 (2011).

    Article  CAS  PubMed  Google Scholar 

  189. Tinsley, J. M. et al. Daily treatment with SMTC1100, a novel small molecule utrophin upregulator, dramatically reduces the dystrophic symptoms in the mdx mouse. PLoS ONE 6, e19189 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Muntoni, F. et al. 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 (2019).

    Article  CAS  PubMed  Google Scholar 

  191. Wilkinson, I. V. L. et al. Chemical proteomics and phenotypic profiling identifies the aryl hydrocarbon receptor as a molecular target of the utrophin modulator ezutromid. Angew. Chem. Int. Ed. 59, 2420–2428 (2020).

    Article  CAS  Google Scholar 

  192. Guiraud, S. et al. Second-generation compound for the modulation of utrophin in the therapy of DMD. Hum. Mol. Genet. 24, 4212–4224 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Tinsley, J. M. et al. Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene. Nature 384, 349–353 (1996).

    Article  CAS  PubMed  Google Scholar 

  194. Deconinck, N. et al. Expression of truncated utrophin leads to major functional improvements in dystrophin-deficient muscles of mice. Nat. Med. 3, 1216–1221 (1997).

    Article  CAS  PubMed  Google Scholar 

  195. Odom, G. L., Gregorevic, P., Allen, J. M., Finn, E. & Chamberlain, J. S. Microutrophin delivery through rAAV6 increases lifespan and improves muscle function in dystrophic dystrophin/utrophin-deficient mice. Mol. Ther. 16, 1539–1545 (2008).

    Article  CAS  PubMed  Google Scholar 

  196. Sengupta, K. et al. Genome editing-mediated utrophin upregulation in Duchenne muscular dystrophy stem cells. Mol. Ther. Nucleic Acids 22, 500–509 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Pisani, C. et al. Utrophin up-regulation by artificial transcription factors induces muscle rescue and impacts the neuromuscular junction in mdx mice. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 1172–1182 (2018).

    Article  CAS  PubMed  Google Scholar 

  198. Li, D. et al. Sarcolemmal nNOS anchoring reveals a qualitative difference between dystrophin and utrophin. J. Cell Sci. 123, 2008–2013 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Belanto, J. J. et al. Microtubule binding distinguishes dystrophin from utrophin. Proc. Natl Acad. Sci. USA 111, 5723–5728 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Markati, T., De Waele, L., Schara-Schmidt, U. & Servais, L. Lessons learned from discontinued clinical developments in Duchenne muscular dystrophy. Front. Pharmacol. 12, 735912 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Markati, T. et al. Emerging therapies for Duchenne muscular dystrophy. Lancet Neurol. 21, 814–829 (2022).

    Article  CAS  PubMed  Google Scholar 

  202. Italfarmaco Group Announces Positive Topline Data From Phase 3 Trial Showing Beneficial Effect Of Givinostat in Patients with Duchenne Muscular Dystrophy (Businesswire, 2022); https://www.businesswire.com/news/home/20220625005001/en/Italfarmaco-Group-Announces-Positive-Topline-Data-from-Phase-3-Trial-Showing-Beneficial-Effect-of-Givinostat-in-Patients-with-Duchenne-Muscular-Dystrophy.

  203. Colussi, C. et al. HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment. Proc. Natl Acad. Sci. USA 105, 19183–19187 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Bettica, P. et al. Histological effects of givinostat in boys with Duchenne muscular dystrophy. Neuromuscul. Disord. 26, 643–649 (2016).

    Article  PubMed  Google Scholar 

  205. Webster, C., Silberstein, L., Hays, A. P. & Blau, H. M. Fast muscle fibers are preferentially affected in Duchenne muscular dystrophy. Cell 52, 503–513 (1988).

    Article  CAS  PubMed  Google Scholar 

  206. Petrof, B. J. et al. Adaptations in myosin heavy chain expression and contractile function in dystrophic mouse diaphragm. Am. J. Physiol. 265, C834–C841 (1993).

    Article  CAS  PubMed  Google Scholar 

  207. Oldfors, A. Hereditary myosin myopathies. Neuromuscul. Disord. 17, 355–367 (2007).

    Article  PubMed  Google Scholar 

  208. Clinical Trials (Edgewise, accessed 2023); https://edgewisetx.com/clinical-trials.

  209. Cordova, G., Negroni, E., Cabello-Verrugio, C., Mouly, V. & Trollet, C. Combined therapies for Duchenne muscular dystrophy to optimize treatment efficacy. Front. Genet. 9, 114 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Verhaart, I. E. C. et al. Prednisolone treatment does not interfere with 2’-O-methyl phosphorothioate antisense-mediated exon skipping in Duchenne muscular dystrophy. Hum. Gene Ther. 23, 262–273 (2012).

    Article  CAS  PubMed  Google Scholar 

  211. Peccate, C. et al. Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles. Hum. Mol. Genet. 25, 3555–3563 (2016).

    Article  CAS  PubMed  Google Scholar 

  212. Kendall, G. C. et al. Dantrolene enhances antisense-mediated exon skipping in human and mouse models of Duchenne muscular dystrophy. Sci. Transl. Med. 4, 164ra160 (2012).

    Article  PubMed  Google Scholar 

  213. Bizot, F. et al. Histone deacetylase inhibitors improve antisense-mediated exon-skipping efficacy in mdx mice. Mol. Ther. Nucleic Acids 30, 606–620 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Guiraud, S. et al. The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy. Hum. Mol. Genet. 28, 2189–2200 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Hayashita-Kinoh, H. et al. Improved transduction of canine X-linked muscular dystrophy with rAAV9-microdystrophin via multipotent MSC pretreatment. Mol. Ther. Methods Clin. Dev. 20, 133–141 (2021).

    Article  CAS  PubMed  Google Scholar 

  216. Roberts, T. C. The microRNA machinery. Adv. Exp. Med. Biol. 887, 15–30 (2015).

    Article  CAS  PubMed  Google Scholar 

  217. Greco, S. et al. Common micro-RNA signature in skeletal muscle damage and regeneration induced by Duchenne muscular dystrophy and acute ischemia. FASEB J. 23, 3335–3346 (2009).

    Article  CAS  PubMed  Google Scholar 

  218. Roberts, T. C. et al. Expression analysis in multiple muscle groups and serum reveals complexity in the microRNA transcriptome of the mdx mouse with implications for therapy. Mol. Ther. Nucleic Acids 1, e39 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Cacchiarelli, D. et al. miR-31 modulates dystrophin expression: new implications for Duchenne muscular dystrophy therapy. EMBO Rep. 12, 136–141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Fiorillo, A. A. et al. TNF-α-induced microRNAs control dystrophin expression in becker muscular dystrophy. Cell Rep. 12, 1678–1690 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Basu, U. et al. Translational regulation of utrophin by miRNAs. PLoS ONE 6, e29376 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Mishra, M. K., Loro, E., Sengupta, K., Wilton, S. D. & Khurana, T. S. Functional improvement of dystrophic muscle by repression of utrophin: let-7c interaction. PLoS ONE 12, e0182676 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Abmayr, S., Gregorevic, P., Allen, J. M. & Chamberlain, J. S. Phenotypic improvement of dystrophic muscles by rAAV/microdystrophin vectors is augmented by Igf1 codelivery. Mol. Ther. 12, 441–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  224. Dumonceaux, J. et al. Combination of myostatin pathway interference and dystrophin rescue enhances tetanic and specific force in dystrophic mdx mice. Mol. Ther. 18, 881–887 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Malerba, A. et al. Dual myostatin and dystrophin exon skipping by morpholino nucleic acid oligomers conjugated to a cell-penetrating peptide is a promising therapeutic strategy for the treatment of Duchenne muscular dystrophy. Mol. Ther. Nucleic Acids 1, e62 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Rodino-Klapac, L. R. et al. Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model. Hum. Mol. Genet. 22, 4929–4937 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Mariot, V. et al. Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches. Nat. Commun. 8, 1859 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Godfrey, C. et al. How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse. Hum. Mol. Genet. 24, 4225–4237 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. van den Bergen, J. C. et al. Dystrophin levels and clinical severity in Becker muscular dystrophy patients. J. Neurol. Neurosurg. Psychiatry 85, 747–753 (2014).

    Article  PubMed  Google Scholar 

  230. Hoffman, E. P. et al. Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology 39, 1011–1017 (1989).

    Article  CAS  PubMed  Google Scholar 

  231. van Westering, T. L. E. et al. Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology. J. Cachexia Sarcopenia Muscle 11, 578–593 (2020).

    Article  PubMed  Google Scholar 

  232. Chwalenia, K. et al. Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties. Mol. Ther. Nucleic Acids 29, 955–968 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Dangouloff, T. & Servais, L. Clinical evidence supporting early treatment of patients with spinal muscular atrophy: current perspectives. Ther. Clin. Risk Manag. 15, 1153–1161 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Thomas, S. et al. Time to diagnosis of Duchenne muscular dystrophy remains unchanged: findings from the Muscular Dystrophy Surveillance, Tracking, and Research Network, 2000-2015. Muscle Nerve 66, 193–197 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford, UK

    Thomas C. Roberts & Matthew J. A. Wood

  2. Department of Paediatrics, University of Oxford, Oxford, UK

    Thomas C. Roberts & Matthew J. A. Wood

  3. MDUK Oxford Neuromuscular Centre, Oxford, UK

    Thomas C. Roberts, Matthew J. A. Wood & Kay E. Davies

  4. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Kay E. Davies

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  3. Kay E. Davies
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The manuscript was conceived by K.E.D. and T.C.R. The first draft was written by T.C.R. All authors researched data for the article. All authors contributed substantially to discussion of the content and edited the manuscript before submission.

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Correspondence to Thomas C. Roberts or Kay E. Davies.

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Competing interests

K.E.D. is a member of the scientific advisory board of Sarepta Therapeutics. M.J.A.W. is an adviser and shareholder in PepGen Ltd and Evox Therapeutics. T.C.R. declares no financial competing interests.

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Nature Reviews Drug Discovery thanks Alessandra Ferlini, Oxana Ibraghimov-Beskrovnaya and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Roberts, T.C., Wood, M.J.A. & Davies, K.E. Therapeutic approaches for Duchenne muscular dystrophy. Nat Rev Drug Discov 22, 917–934 (2023). https://doi.org/10.1038/s41573-023-00775-6

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