Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches

Nature Reviews Genetics volume 14, pages 373–378 (2013)Cite this article

Subjects

Abstract

Duchenne muscular dystrophy (DMD) is a devastating progressive disease for which there is currently no effective treatment except palliative therapy. There are several promising genetic approaches, including viral delivery of the missing dystrophin gene, read-through of translation stop codons, exon skipping to restore the reading frame and increased expression of the compensatory utrophin gene. The lessons learned from these approaches will be applicable to many other disorders.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The dystrophin-associated protein complex.
Figure 2: Dystrophin, utrophin and genetic approaches to therapy.

References

  1. Emery, A. E. H. Muscular Dystrophy (The Facts) (Oxford Univ. Press, 2008).

    Google Scholar 

  2. Cohn, R. D. & Campbell, K. P. Molecular basis of muscular dystrophies. Muscle Nerve 23, 1456–1471 (2000).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  4. Fairclough, R. J., Perkins, K. J. & Davies, K. E. Pharmacologically targeting the primary defect and downstream pathology in Duchenne muscular dystrophy. Curr. Gene Ther. 12, 206–244 (2012).

    Article  CAS  Google Scholar 

  5. Neri, M. et al. Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human. Neuromuscul. Disord. 17, 913–918 (2007).

    Article  Google Scholar 

  6. Cavazzana-Calvo, M. & Fischer, A. Gene therapy for severe combined immunodeficiency: are we there yet? J. Clin. Invest. 117, 1456–1465 (2007).

    Article  CAS  Google Scholar 

  7. Vandenberghe, L. H. & Auricchio, A. Novel adeno-associated viral vectors for retinal gene therapy. Gene Ther. 19, 162–168 (2012).

    Article  CAS  Google Scholar 

  8. Buchlis, G. et al. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood 119, 3038–3041 (2012).

    Article  CAS  Google Scholar 

  9. Pichavant, C. et al. Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Mol. Ther. 19, 830–840 (2011).

    Article  CAS  Google Scholar 

  10. Lai, Y. et al. 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 (2009).

    Article  CAS  Google Scholar 

  11. Mendell, J. R. et al. Gene therapy for muscular dystrophy: lessons learned and path forward. Neurosci. Lett. 527, 90–99 (2012).

    Article  CAS  Google Scholar 

  12. Mendell, J. R. et al. Sustained α-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann. Neurol. 68, 629–638 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Wang, Z. et al. 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 (2012).

    Article  CAS  Google Scholar 

  15. Bidou, L., Allamand, V., Rousset, J. P. & Namy, O. Sense from nonsense: therapies for premature stop codon diseases. Trends Mol. Med. 18, 679–688 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Finkel, R. S. Read-through strategies for suppression of nonsense mutations in Duchenne/Becker muscular dystrophy: aminoglycosides and ataluren (PTC124). J. Child Neurol. 25, 1158–1164 (2010).

    Article  Google Scholar 

  18. McDonald, C. M. et al. The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve 41, 500–510 (2010).

    Article  Google Scholar 

  19. Kayali, R. et al. Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy. Hum. Mol. Genet. 21, 4007–4020 (2012).

    Article  CAS  Google Scholar 

  20. Bordeira-Carrico, R., Pego, A. P., Santos, M. & Oliveira, C. Cancer syndromes and therapy by stop-codon readthrough. Trends Mol. Med. 18, 667–678 (2012).

    Article  CAS  Google Scholar 

  21. Muntoni, F. & Wood, M. J. Targeting RNA to treat neuromuscular disease. Nature Rev. Drug Discov. 10, 621–637 (2011).

    Article  CAS  Google Scholar 

  22. Kinali, M. et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 8, 918–928 (2009).

    Article  CAS  Google Scholar 

  23. van Deutekom, J. C. et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N. Engl. J. Med. 357, 2677–2686 (2007).

    Article  CAS  Google Scholar 

  24. Cirak, S. et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet 378, 595–605 (2011).

    Article  CAS  Google Scholar 

  25. Goemans, N. M. et al. Systemic administration of PRO051 in Duchenne's muscular dystrophy. N. Engl. J. Med. 364, 1513–1522 (2011).

    Article  CAS  Google Scholar 

  26. Betts, C. A., Hammond, S. M., Yin, H. F. & Wood, M. J. Optimizing tissue-specific antisense oligonucleotide-peptide conjugates. Methods Mol. Biol. 867, 415–435 (2012).

    Article  CAS  Google Scholar 

  27. Mitrpant, C. et al. Rational design of antisense oligomers to induce dystrophin exon skipping. Mol. Ther. 17, 1418–1426 (2009).

    Article  CAS  Google Scholar 

  28. 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  Google Scholar 

  29. Cacchiarelli, D. et al. miRNAs as serum biomarkers for Duchenne muscular dystrophy. EMBO Mol. Med. 3, 258–265 (2011).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  31. Nadarajah, V. D. et al. Serum matrix metalloproteinase-9 (MMP-9) as a biomarker for monitoring disease progression in Duchenne muscular dystrophy (DMD). Neuromuscul. Disord. 21, 569–578 (2011).

    Article  CAS  Google Scholar 

  32. Zammarchi, F. et al. Antitumorigenic potential of STAT3 alternative splicing modulation. Proc. Natl Acad. Sci. USA 108, 17779–17784 (2011).

    Article  CAS  Google Scholar 

  33. Khurana, T. S. & Davies, K. E. Pharmacological strategies for muscular dystrophy. Nature Rev. Drug Discov. 2, 379–390 (2003).

    Article  CAS  Google Scholar 

  34. Miura, P. & Jasmin, B. J. Utrophin upregulation for treating Duchenne or Becker muscular dystrophy: how close are we? Trends Mol. Med. 12, 122–129 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Ramachandran, J. et al. Nitric oxide signaling pathway in Duchenne muscular dystrophy mice: upregulation of l-arginine transporters. Biochem. J. (2012).

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

    Article  CAS  Google Scholar 

  38. Kleopa, K. A., Drousiotou, A., Mavrikiou, E., Ormiston, A. & Kyriakides, T. Naturally occurring utrophin correlates with disease severity in Duchenne muscular dystrophy. Hum. Mol. Genet. 15, 1623–1628 (2006).

    Article  CAS  Google Scholar 

  39. Sonnemann, K. J. et al. Functional substitution by TAT-utrophin in dystrophin-deficient mice. PLoS Med. 6, e1000083 (2009).

    Article  Google Scholar 

  40. Chakkalakal, J. V., Miura, P., Belanger, G., Michel, R. N. & Jasmin, B. J. 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 (2008).

    Article  CAS  Google Scholar 

  41. Moorwood, C., Soni, N., Patel, G., Wilton, S. D. & Khurana, T. S. A cell-based high-throughput screening assay for posttranscriptional utrophin upregulation. J. Biomol. Screen. 18, 400–406 (2012).

    Article  Google Scholar 

  42. 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  Google Scholar 

  43. Amenta, A. R. et al. Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice. Proc. Natl Acad. Sci. USA 108, 762–767 (2011).

    Article  CAS  Google Scholar 

  44. Angus, L. M. et al. Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1α, drives utrophin gene expression at the neuromuscular junction. Am. J. Physiol. Cell Physiol. 289, C908–C917 (2005).

    Article  CAS  Google Scholar 

  45. Handschin, C. et al. PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev. 21, 770–783 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  47. van Putten, M. et al. Low dystrophin levels increase muscle survival and improve muscle pathology and function in dystrophin/utrophin double-knock-out mice. FASEB J. 4 Mar 2013 (10.1096/fj.12-224170).

  48. Gambari, R. & Fibach, E. Medicinal chemistry of fetal hemoglobin inducers for treatment of β-thalassemia. Curr. Med. Chem. 14, 199–212 (2007).

    Article  CAS  Google Scholar 

  49. Hirawat, S. et al. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J. Clin. Pharmacol. 47, 430–444 (2007).

    Article  CAS  Google Scholar 

  50. Heemskerk, H. A. et al. In vivo comparison of 2′-O-methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping. J. Gene Med. 11, 257–266 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are very grateful to the UK Medical Research Council, the Wellcome Trust, the UK Muscular Dystrophy Campaign, the US Muscular Dystrophy Association, Action Duchenne, the Association Française Contre les Myopathies and the International Consortium on Exon Skipping for support.

Author information

Authors and Affiliations

  1. Matthew J. Wood and Kay E. Davies are at the Department of Physiology, Rebecca J. Fairclough, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.,

    Rebecca J. Fairclough, Matthew J. Wood & Kay E. Davies

  2. Department of Physiology, Rebecca J. Fairclough and Kay E. Davies are also at the MRC Functional Genomics Unit, MRC Functional Genomics Unit, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK.,

    Rebecca J. Fairclough & Kay E. Davies

Authors
  1. Rebecca J. Fairclough
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew J. Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kay E. Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kay E. Davies.

Ethics declarations

Competing interests

Kay E. Davies is on the scientific advisory board of Prosensa plc and Summit plc. Rebecca J. Fairclough and Matthew J. Wood declare no competing financial interests.

Related links

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fairclough, R., Wood, M. & Davies, K. Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches. Nat Rev Genet 14, 373–378 (2013). https://doi.org/10.1038/nrg3460

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3460

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research