Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping.
Most mutations in the dystrophin gene create a frameshift or a stop in the mRNA and are associated with severe Duchenne muscular dystrophy. Exon skipping that naturally occurs at low frequency sometimes eliminates the mutation and leads to the production of a rescued protein. We have achieved persistent exon skipping that removes the mutated exon on the dystrophin messenger mRNA of the mdx mouse, by a single administration of an AAV vector expressing antisense sequences linked to a modified U7 small nuclear RNA. We report the sustained production of functional dystrophin at physiological levels in entire groups of muscles and the correction of the muscular dystrophy.
Goyenvalle
Aurélie
A
Généthon & CNRS UMR 8115, 1, rue de l'Internationale, Evry, France.
Vulin
Adeline
A
Fougerousse
Françoise
F
Leturcq
France
F
Kaplan
Jean-Claude
JC
Garcia
Luis
L
Danos
Olivier
O
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D015316:Genetic Therapy; D005822:Genetic Vectors; D007438:Introns; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000276:immunology / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012342:RNA, Small Nuclear / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D016189:Dystrophin; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012342:RNA, Small Nuclear; C405487:U7 small nuclear RNA