Résumé :
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In Duchenne Muscular Dystrophy (DMD) the selective removal by exon skipping of exons flanking an out-of frame mutation in the dystrophin messenger can result in in-frame mRNA transcripts that are translated into shorter but functionally active dystrophin.In 7 Golden Retriever Muscular Dystrophy (GRMD) dogs, a recombinant Adeno-Associated Virus serotype 8 (rAAV8) expressing a optimized U7 snRNA specific for the correction of the GRMD dystrophin transcript has been delivered by locoregional high-pressure intravenous (IV) injection of a forelimb. Three months later, all the forelimb muscles (32) and 14 other muscles were sampled and percentages of dystrophin positive fibers were determined on each muscle revealing the distribution of efficiency of transduction.Maps of the muscular distribution of transduction were established and analyzed for the different rAAV8-U7snRNA doses (2.5 E12 to 2.5 E13 vg/kg). We demonstrate a strong efficiency of the locoregional injection strategy to express truncated dystrophin. Relationships between the number of vector copies and percentage of dystrophin positive fibers are established. Variations of the efficiency depending of the vascular muscle supply were also assessed.This project is supported by AFM (Association Franse contre les Myopathies) and by ADNA (Advanced Diagnostics for New Therapeutic Approaches), a program dedicated to personalized medicine, coordinated by Institut Meux and supported by research and innovation aid from the French public agency, OSEO
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