0 avis
Effective Limb Transduction and Phenotypic Correction after Injection of rAAV8-U7 snRNA in GRMD Dogs
Archive ouverte
Edité par CCSD ; Nature Publishing Group -
In Duchenne Muscular Dystrophy (DMD) the selective removal by exon skipping of exons anking 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. The goal of our project was to determine in GRMD, the effective dose of our therapeutic product de ned as a recombinant Adeno-Associated Virus serotype 8 (rAAV8) expressing a modified U7 snRNA speci c for the skipping of exons 5 to 10 of the GRMD dystrophin transcript. The mode of delivery was the locoregional high-pressure intravenous (IV) injection of a forelimb. Several groups of GRMD dogs were exposed to different rAAV8-U7snRNA doses. Each dog was followed ∼3 months after injection. The primary outcomes were the restoration of dystrophin expression and the improvement of the tissue pathology in the injected limb compared to the controlateral limb. The secondary outcomes were the muscle strength correction, the biodistribution and shedding patterns as well as the immune response against rAAV8 capsid and dystrophin. Our preliminary results suggest a dose effect of our therapeutic rAAV. Injection of 2,5E13vg/kg and of 5E12vg/kg of our vector was able to restore 50 to 80% of Dystrophin expression in the injected limb. This expression of a semi-functional dystrophin resulted in improvement of tissue morphology as well as of several functional and MRI parameters. No tissue in ammation occurred following the procedure. We built a unique network of laboratories with complementary skills to deliver a GLP-compliant set of preclinical data to further de ne the regulatory toxicology studies. The organization of our network and the results obtained in our GRMD dogs study will be presented. This project is supported by AFM (Association Française contre les Myopathies) and by ADNA (Advanced Diagnostics for New Therapeutic Approaches), a program dedicated to personalized medicine, coordinated by Institut Mérieux and supported by research and innovation aid from the French public agency, OSEO.
Consulter en ligne
Suggestions
Du même auteur
