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Muscular dystrophy

New exon-skipping strategy rescues dystrophin

Nature Reviews Drug Discovery volume 14, pages 236–237 (2015)Cite this article

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Exon skipping using AONs coaxes the cell's transcriptional machinery to skip over a targeted exon, to restore an open reading frame and allow expression of a truncated but functional protein. However, in DMD, recent clinical trials testing either 2′-O-methyl-modified oligoribonucleotides (2′OMes) or phosphorodiamidate morpholino oligomers (PMOs) have failed to show marked clinical benefit, probably owing to insufficient dystrophin rescue. Goyenvalle and colleagues therefore set out to investigate the therapeutic potential of a new DNA analogue, tcDNA — a conformationally constrained oligonucleotide analogue that, compared to natural DNA, has three additional carbon atoms between C5′ and C3′ that result in improved pharmacological properties.

First, the authors intravenously administered a tcDNA-AON targeting Dmd exon 23 to a mouse model of DMD (mdx mice, which carry a nonsense mutation in exon 23 of the Dmd gene) for 12 weeks. The tcDNA-AON was stable and detected in all tested skeletal muscles as well as the heart and brain. Quantitative PCR revealed effective skipping of exon 23 to levels 5- to 6-fold higher than those achieved with 2′OMe- and PMO-AONs. Importantly, this translated into a greater rescue of dystrophin protein levels, particularly in the diaphragm and heart (where levels reached 50% and 40%, respectively), than found in wild-type mice. Notably, exon 23 skipping and dystrophin protein expression were seen in the CNS of only those animals treated with tcDNA-AON.

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References

  1. Goyenvalle, A. et al. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nature Med. http://dx.doi.org/10.1038/nm.3765 (2015)

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  1. Sarah Crunkhorn
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Crunkhorn, S. New exon-skipping strategy rescues dystrophin. Nat Rev Drug Discov 14, 236–237 (2015). https://doi.org/10.1038/nrd4587

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