title: Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse.
abstract: As a target for gene therapy, Duchenne muscular dystrophy (DMD) presents many obstacles but also an unparalleled prospect for correction by alternative splicing. The majority of mutations in the dystrophin gene occur in the region encoding the spectrin-like central rod domain, which is largely dispensable. Thus, splicing around mutations can generate a shortened but in-frame transcript, permitting translation of a partially functional dystrophin protein. We have tested this idea in vivo in the mdx dystrophic mouse (carrying a mutation in exon 23 of the dystrophin gene) by combining a potent transfection protocol with a 2-O-methylated phosphorothioated antisense oligoribonucleotide (2OMeAO) designed to promote skipping of the mutated exon*. The treated mice show persistent production of dystrophin at normal levels in large numbers of muscle fibers and show functional improvement of the treated muscle. Repeated administration enhances dystrophin expression without eliciting immune responses. Our data establishes the realistic practicality of an approach that is applicable, in principle, to a majority of cases of severe dystrophinopathy.
authors.affiliation: Muscle Cell Biology, MRC Clinical Science Centre, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. qi.long-lu@csc.mrc.ac.uk
authors.forename: Qi Long
authors.initials: QL
authors.lastname: Lu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mann
authors.forename: Fang
authors.initials: F
authors.lastname: Lou
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Morris
authors.forename: Shao-an
authors.initials: SA
authors.lastname: Xue
authors.forename: Sue
authors.initials: S
authors.lastname: Fletcher
authors.forename: Terence A
authors.initials: TA
authors.lastname: Partridge
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wilton
mesh_terms: D000818:Animals; D016189:Dystrophin / Q000235:genetics*; D005091:Exons; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000628:therapy*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000628:therapy*; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D012326:RNA Splicing
chemical_list: D016189:Dystrophin; D016376:Oligonucleotides, Antisense