title: Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping.
abstract: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder resulting from lesions of the gene encoding dystrophin. These usually consist of large genomic deletions, the extents of which are not correlated with the severity of the phenotype. Out-of-frame deletions give rise to dystrophin deficiency and severe DMD phenotypes, while internal deletions that produce in-frame mRNAs encoding truncated proteins can lead to a milder myopathy known as Becker muscular dystrophy (BMD). Widespread restoration of dystrophin expression via adeno-associated virus (AAV)-mediated exon skipping has been successfully demonstrated in the mdx mouse model and in cardiac muscle after percutaneous transendocardial delivery in the golden retriever muscular dystrophy dog (GRMD) model. Here, a set of optimized U7snRNAs carrying antisense sequences designed to rescue dystrophin were delivered into GRMD skeletal muscles by AAV1 gene transfer using intramuscular injection or forelimb perfusion. We show sustained correction of the dystrophic phenotype in extended muscle areas and partial recovery of muscle strength. Muscle architecture was improved and fibers displayed the hallmarks of mature and functional units. A 5-year follow-up ruled out immune rejection drawbacks but showed a progressive decline in the number of corrected muscle fibers, likely due to the persistence of a mild dystrophic process such as occurs in BMD phenotypes. Although AAV-mediated exon skipping was shown safe and efficient to rescue a truncated dystrophin, it appears that recurrent treatments would be required to maintain therapeutic benefit ahead of the progression of the disease.
authors.affiliation: UPMC Um76, Inserm U974, CNRS UMR7215, Institut de Myologie, 105 Bd de l'Hôpital, Paris, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Vulin
authors.forename: Inès
authors.initials: I
authors.lastname: Barthélémy
authors.forename: Aurélie
authors.initials: A
authors.lastname: Goyenvalle
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Thibaud
authors.forename: Cyriaque
authors.initials: C
authors.lastname: Beley
authors.forename: Graziella
authors.initials: G
authors.lastname: Griffith
authors.forename: Rachid
authors.initials: R
authors.lastname: Benchaouir
authors.forename: Maëva
authors.initials: M
authors.lastname: le Hir
authors.forename: Yves
authors.initials: Y
authors.lastname: Unterfinger
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lorain
authors.forename: Patrick
authors.initials: P
authors.lastname: Dreyfus
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Pierre
authors.initials: P
authors.lastname: Carlier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blot
authors.forename: Luis
authors.initials: L
authors.lastname: Garcia
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D016189:Dystrophin / Q000235:genetics*; D005091:Exons; D005552:Forelimb / Q000503:physiopathology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D007273:Injections, Intramuscular; D008969:Molecular Sequence Data; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000503:physiopathology / Q000628:therapy*; D020320:Oligoribonucleotides, Antisense / Q000235:genetics*; D012342:RNA, Small Nuclear / Q000235:genetics*; D014158:Transcription, Genetic; D049411:Utrophin / Q000235:genetics / Q000378:metabolism
chemical_list: D016189:Dystrophin; D020320:Oligoribonucleotides, Antisense; D012342:RNA, Small Nuclear; C405487:U7 small nuclear RNA; D049411:Utrophin; D002118:Calcium