Résumé :
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Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder due to mutations in the gene encoding dystrophin. Most of mutations consist in large deletions, although their size is not correlated with the severity of the phenotype. Out-of-frame deletions lead to dystrophin deficiency and severe DMD phenotypes, while internal deletions producing in frame mRNAs and consequently shorter proteins are responsible for a milder phenotype known as Becker Muscular Dystrophy (BMD). Attractively, about 80% of the out-of-frame mutations could be theoretically rescued after restoring the translational frame by using exon skipping strategies. Here we have combined a set of optimized U7snRNA and AAV gene transfer to achieve the precise skipping of multiple exons spaced over 125,000 nucleotides of the dystrophin pre-mRNA and the re-expression of a functional protein in the Golden Retriever Muscular Dystrophy (GRMD) dog. This led to a sustained correction of the dystrophic phenotype over extended muscle areas and recovery of muscle strength. Muscle architecture was corrected and fibres displayed the hallmarks of mature and functional units. Our study documents for the first time the recovery of normal muscle function in a large animal model after dystrophin rescue and thus represents a critical milestone for the development of clinical trials. 1. UPMC Inserm UMR S 787, Institut de Myologie, 105 Bd de l'Hôpital, Paris, France 2. Laboratoire de Neurobiologie ENVA, 7 Avenue du Général de Gaulle, Maisons Alfort, France 3. Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK 4. Laboratoire RMN AIM-CEA, Institut de Myologie, Hôpital Pitié-Salpêtrière, Paris, France 5. Inserm U781, Hôpital Necker-Enfants Malades & Université Paris Descartes, Paris, France
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