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Therapeutic approaches for Duchenne muscular dystrophy

Nature Reviews Drug Discovery volume 22, pages 917–934 (2023)Cite this article

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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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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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Contributions

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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