Editors' ChoiceDuchenne Muscular Dystrophy

A molecular patch for DMD

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Science Translational Medicine  11 Feb 2015:
Vol. 7, Issue 274, pp. 274ec24
DOI: 10.1126/scitranslmed.aaa8311

Antisense oligonucleotides (AONs)—small DNA fragments used to mask exons so that they are skipped during translation—serve as a sort of molecular patch. This method of exon skipping is currently being tested in clinical trials for treating neuromuscular disorders by preventing exons with nonsense mutations from stalling translation. However, for diseases where whole-body treatment is needed, the current AONs show limited success due to poor tissue uptake and insufficient therapeutic efficacy.

In the present study, the Goyenvalle et al. have designed a new AON, tricyclo-DNA (tcDNA), with improved pharmacological properties and uptake by many tissues after systemic administration in mouse models of Duchenne muscular dystrophy (DMD). DMD, an X-linked recessive form of dystrophy, is caused by mutations in the dystrophin gene, which functions to stabilize and protect muscle fibers. Nonsense mutations in this gene lead to damage in muscle cells, muscle degeneration, and eventually death. In the current study, tcDNA is used to mask exon 23 of the dystrophin gene in two mouse models of DMD (mdx phenotype). The patch results in higher exon skipping and increased levels of dystrophin in cardiac and respiratory systems. Mice treated with tcDNA also showed reduced muscle damage and improved behavior. These data provide strong evidence that tcDNA may rescue dystrophin and revert the mdx phenotype. The improved efficacy and uptake of tcDNA in comparison to other AONs may be attributed to the fact that it forms nanoparticles (40 to100 nm in size) and demonstrates self-association properties similar to transfection agents. Although the authors have not observed any toxic effects of tcDNA in treated mice, the tolerance of these AONs in human needs to be tested.

This is the first study where exon skipping represents a viable and efficient approach to rescue dystrophin levels in various tissues, leading to functional improvement in mouse model of DMD. Thus, tcDNA offers not only a potential new therapeutic approach for DMD, but also for other multisystemic disorders suited for exon skipping.

A. Goyenvalle et al., Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat. Med. 10.1038/nm.3765 (2015). [Full Text]

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