Optimizing exon skipping therapies for DMD

Exon skipping is one of the more promising therapeutic options for Duchenne Muscular Dystrophy (DMD). The idea is to use antisense oligonucleotides to splice out selected exons from the pre-mRNA, at or next to the mutation site, so as to generate a translatable transcript from the mutant dystrophin gene. In principle, the majority of DMD mutations can be rescued by targeting selected exons. Recent developments of antisense oligonucleotides (AOs) such as 2O-methylated antisense oligonucleotides (2OMeAOs) or phosphorodiamidate morpholino oligomers (morpholinos, PMOs) have made it possible to restore dystrophin expression body-wide in dystrophic mice and dystrophic dogs by single or multi-exon skipping with no obvious side-effect. Since such treatment would, in many cases, require bespoke design of AOs, it is important to demonstrate treatment of a variety of mutations in dystrophic animals. In-frame deletion patterns usually result in a mix of Duchenne and milder Becker Muscular Dystrophy (BMD), but the ratio of Duchenne to Becker varies between patterns, and this provides useful information for selection of the exons that might most profitably be targeted. This review summarizes recent progress in exon skipping therapy and discusses future strategies.