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Activating internal ribosome entry to treat Duchenne muscular dystrophy

Nature Medicine volume 20, pages 987–988 (2014)Cite this article

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Mutations in the DMD gene, encoding dystrophin, cause the most common forms of muscular dystrophy. A new study shows that forcing translation of DMD from an internal ribosome entry site can alleviate Duchenne muscular dystrophy symptoms in a mouse model.

Duchenne muscular dystrophy (DMD) is characterized by complete or almost complete loss of dystrophin, an intracellular muscle structural protein that is a crucial component of the major connection between the internal cytoskeleton and the extracellular basement membrane. Children with DMD present in early childhood with progressive muscle weakness leading to loss of ambulation and early death due to respiratory or cardiac failure. In most patients, genotype-phenotype relationships follow the 'reading frame rule'1, where mutations that disrupt the translational reading frame and introduce premature translation termination codons result in little or no protein production and cause DMD. Mutations in DMD that preserve the open reading frame and protein synthesis usually result in Becker muscular dystrophy (BMD), a less severe disorder in which a truncated form of the protein is produced. Restoration of the reading frame is the principle underlying the exon-skipping approach to DMD therapy, currently in clinical trials2, which aims to produce a truncated functional dystrophin protein and convert the DMD phenotype to a BMD phenotype.

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Figure 1: Exon 2 skipping in a DMD mouse model with an exon 2 duplication can ameliorate the DMD phenotype.

Debbie Maizels/Nature Publishing Group

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Authors and Affiliations

  1. Shireen R. Lamandé and Kathryn N. North are in the Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.,

    Shireen R Lamandé & Kathryn N North

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  1. Shireen R Lamandé
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  2. Kathryn N North
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Correspondence to Kathryn N North.

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The authors declare no competing financial interests.

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Lamandé, S., North, K. Activating internal ribosome entry to treat Duchenne muscular dystrophy. Nat Med 20, 987–988 (2014). https://doi.org/10.1038/nm.3677

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