Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Dependovirus / genetics
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Dystrophin / genetics*
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Dystrophin / metabolism
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Exons*
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Genetic Therapy*
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Genetic Vectors
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Introns
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Mice
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Mice, Inbred mdx
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Muscle Contraction
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Muscle Fibers, Skeletal / immunology
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Muscle Fibers, Skeletal / pathology
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology
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Muscle, Skeletal / physiology
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Muscular Dystrophy, Animal / genetics
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Muscular Dystrophy, Animal / pathology
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Muscular Dystrophy, Animal / physiopathology
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Muscular Dystrophy, Animal / therapy*
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Muscular Dystrophy, Duchenne / genetics
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Muscular Dystrophy, Duchenne / pathology
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Muscular Dystrophy, Duchenne / physiopathology
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Muscular Dystrophy, Duchenne / therapy*
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Mutation*
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Oligonucleotides, Antisense / pharmacology*
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RNA Splicing
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Nuclear / genetics
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RNA, Small Nuclear / metabolism*
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Transfection
Substances
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Dystrophin
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Oligonucleotides, Antisense
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RNA, Messenger
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RNA, Small Nuclear
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U7 small nuclear RNA