Rational design of antisense oligomers to induce dystrophin exon skipping.
Duchenne muscular dystrophy (DMD), one of the most severe neuromuscular disorders of childhood, is caused by the absence of a functional dystrophin. Antisense oligomer (AO) induced exon skipping is being investigated to restore functional dystrophin expression in models of muscular dystrophy and DMD patients. One of the major challenges will be in the development of clinically relevant oligomers and exon skipping strategies to address many different mutations. Various models, including cell-free extracts, cells transfected with artificial constructs, or mice with a human transgene, have been proposed as tools to facilitate oligomer design. Despite strong sequence homology between the human and mouse dystrophin genes, directing an oligomer to the same motifs in both species does not always induce comparable exon skipping. We report substantially different levels of exon skipping induced in normal and dystrophic human myogenic cell lines and propose that animal models or artificial assay systems useful in initial studies may be of limited relevance in designing the most efficient compounds to induce targeted skipping of human dystrophin exons for therapeutic outcomes.
Mitrpant
Chalermchai
C
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, QE II Medical Centre, Nedlands, Western Australia, Australia.
Adams
Abbie M
AM
Meloni
Penny L
PL
Muntoni
Francesco
F
Fletcher
Sue
S
Wilton
Steve D
SD
D000818:Animals; D002478:Cells, Cultured; D015195:Drug Design; D016189:Dystrophin / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D006801:Humans; D051379:Mice; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000494:pharmacology*; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D016189:Dystrophin; D016376:Oligonucleotides, Antisense