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Therapeutic alternative splicing: an update on Duchenne muscular dystrophy clinical trials and other applications
Journal article   Peer reviewed

Therapeutic alternative splicing: an update on Duchenne muscular dystrophy clinical trials and other applications

S. Wilton, A. Adams, K. Greer, K.A. West and S. Fletcher
The Journal of Gene Medicine, Vol.17(8 - 9), O19
2015
DOI: https://doi.org/10.1002/jgm.2834
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Abstract

Antisense oligomers (AO) can induce alternative splicing by either blocking positive exon enhancer elements to excise a targeted exon, or masking splice silencer motifs to promote retention of an exon normally excluded from the mature mRNA. We have developed a novel AO‐based treatment for Duchenne muscular dystrophy (DMD) by removing exons associated with protein‐truncating mutations. Targeting dystrophin exon 51 for excision during pre‐mRNA processing will restore the reading frame and functional dystrophin expression in the most common subset of DMD deletion patients. An extended Phase 2 study, initiated by Sarepta Therapeutics in Nationwide Children's Hospital, Columbus, Ohio, has been underway for over 3 years. Treated boys (average age now 13 years) have maintained similar levels of ambulation over the trial period, and their respiratory performance (maximum inspiratory pressure and maximum exhalation pressure) has remained unchanged. No treatment related adverse events have been reported to date. This trial remains ongoing, with additional trials commencing in the UK and the USA. The loss of exon identity, and/or intron definition, is a more common basis for human disease than had been previously appreciated. One study reported that approximately 25% of known pathogenic nonsense or missense mutations caused abnormal pre‐mRNA processing, most commonly exon loss. Using DMD exon switching as an exemplar, we are now pursuing therapeutic alternative splicing for other DMD mutations, as well as unrelated disorders. Amenability to splice intervention may be dependent more on the nature of the mutation and consequence on pre‐mRNA processing than the gene itself.

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