Personalized exon skipping strategies to address clustered non-deletion dystrophin mutations

Antisense oligomer induced exon skipping is showing promise as a therapy to reduce the severity of Duchenne muscular dystrophy To date the focus has been on excluding single exons flanking frame-shifting deletions in the dystrophin gene However a third of all Duchenne muscular dystrophy causing mutations are more subtle DNA changes Thirty nine dystrophin exons are potentially frame-shifting and mutations in these will require the targeted removal of exon blocks to generate in-frame transcripts We report that clustered non-deletion mutations in the dystrophin gene respond differently to different antisense oligomer preparations targeting the same dual exon block the removal of which bypasses the mutation and restores the open reading-frame The personalized nature of the responses to antisense oligomer application presents additional challenges to the induction of multi-exon skipping with a single oligomer preparation Crown Copyright (C) 2010 Published by Elsevier B V All rights reserved