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.
Forrest
Sarah
S
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, WA 6009, Australia.
Meloni
Penny L
PL
Muntoni
Francesco
F
Kim
Jihee
J
Fletcher
Sue
S
Wilton
Steve D
SD
D016189:Dystrophin / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000628:therapy*; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D016133:Polymerase Chain Reaction
D016189:Dystrophin; D016376:Oligonucleotides, Antisense
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