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Therapeutic developments for Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is caused by the lack of functional dystrophin protein. Improvements in patient care and disease management have slowed down disease progression, but current treatments cannot stop the relentless loss of muscle tissue and function, which leads to premature death. Research is ongoing to develop effective therapies for DMD. Gene-addition, exon-skipping, stop codon readthrough and genome-editing therapies can restore the expression of partially functional dystrophin protein, whereas other therapeutic approaches aim to improve muscle function and quality by targeting pathways involved in the pathogenesis of DMD. This Review outlines important developments in these research areas and specifically focuses on new therapies that are in the clinical trial phase or have already been approved.

Key points

  • Duchenne muscular dystrophy (DMD) is a severe, progressive disease caused by lack of dystrophin protein.

  • Secondary consequences of the lack of dystrophin include disturbances in many different physiological pathways, which all offer potential therapeutic targets.

  • Many therapeutic approaches aiming at dystrophin restoration or improvements in muscle quality are being tested in clinical trials.

  • Two therapies addressing the primary defect have been approved (ataluren and eteplirsen); however, their benefits are limited.

  • First results of gene-addition therapy using microdystrophins are promising.

  • Effective treatment for DMD is likely to require combinations of therapies that address both the primary defect and its secondary consequences.

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Fig. 1: Primary and secondary therapies for Duchenne muscular dystrophy.
Fig. 2: Full-length dystrophin protein and microdystrophins tested in gene-addition therapies.

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Acknowledgements

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Nature Reviews Neurology thanks D. Duan and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Annemieke Aartsma-Rus.

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A.A.-R. declares that she is named as an inventor on and receives royalties in relation to patents owned by her employer, Leiden University Medical Centre (LUMC), on exon-skipping technology, some of which have been licensed to BioMarin Pharmaceuticals and sublicensed to Sarepta. A.A.-R. also declares that she has acted as a consultant for BioClinica, BioMarin Pharmaceuticals, Eisai, Gerson Lehrman Group Consultancy, Global Guidepoint, Grunenthal, PTC Therapeutics, Sarepta and Wave and that she has been a member of the Duchenne Network Steering Committee for BioMarin and a member of the scientific advisory boards of Philae Pharmaceuticals and ProQR. Remuneration for these activities of A.A.-R., as well speaker’s honoraria from PTC Therapeutics and BioMarin Pharmaceuticals, is paid to LUMC. I.E.C.V. declares no competing interests.

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Glossary

Transrepression

A trans-acting process whereby one protein inhibits the activity of a different protein via a protein–protein interaction. When the repressed protein is a transcription factor that drives the expression of multiple genes, transrepression results in downregulation of those genes. The beneficial effects of glucocorticoids are attributed to decreased expression of pro-inflammatory genes, especially those encoding transcription factors AP-1 and nuclear factor-κB (NF-κB).

Transactivation

In the context of gene regulation, transactivation refers to increased gene expression triggered indirectly or directly by endogenous or exogenous means. The adverse effects of glucocorticoids are largely attributed to increased expression of particular genes.

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Verhaart, I.E.C., Aartsma-Rus, A. Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol 15, 373–386 (2019). https://doi.org/10.1038/s41582-019-0203-3

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