Splice-switching as a treament for duchenne muscular dystrophy

Abstract

Antisense oligomer manipulation of pre-mRNA splicing can be used to remove exons carrying premature stop codons or to restore the reading frame around frame-shifting mutations. Phase 1 clinical trials have demonstrated that antisense oligomer-mediated splicing manipulation can restore dystro-phin expression in muscle in a subset of Duchenne muscular dystrophy (DMD) patients. The complexities of dystrophin gene expression and widespread distribution of the protein have presented major challenges to gene and cell therapies for DMD. However, the size of the dystrophin gene, and the fact that not all of the 79 exons are necessary to encode a protein with at least partial function, make DMD amenable to splice switching intervention. While dystrophin deletions are clustered in two hotspots, non-deletion mutations are spread throughout the gene. Although 10 oligomers will be required to restore the reading-frame around the more common deletions, numerous compounds are required to by-pass the many different mutations that cause DMD. We have developed compounds to remove each of the dystrophin exons and are currently optimising preparations to remove in-frame blocks of exons to optimise induced dystrophin isoform function. The next challenge will be to extend the application of antisense oligomers to other conditions that may benefit from splice switching.