G.P.92

Autor: Yan Cherel, Philippe Veron, F. Barnay-Toutain, Virginie Latournerie, Christian Leborgne, Jean-Laurent Thibaud, Marie Montus, Claire Wary, Nicolas Jaulin, C. Le Guiner, Claire Domenger, Christel Rivière, Oumeya Adjali, H. Goubin, T. Voit, Carole Masurier, Lydie Guigand, N. Delaunay, Philippe Moullier, Sylvie Boutin, Diana Desgue, B. Matot, Gisèle Bonne, Virginie François, J.Y. Hogrel, Maeva Dutilleul, L. Servais, Pierre G. Carlier, Marie Devaux, M. Allais, Sophie Moullec, J. Le Duff, Mickaël Guilbaud, Jack-Yves Deschamps, T. Larche
Rok vydání: 2014
Předmět:
Zdroj: Neuromuscular Disorders. 24:822
ISSN: 0960-8966
Popis: We have previously demonstrated that a recombinant adeno-associated virus vector, serotype 8 (rAAV8) carrying a modified U7snRNA sequence promoting exon skipping injected in GRMD by locoregional transvenous perfusion of the forelimb, restores up to 80% dystrophin expression and improves histological, Nuclear Magnetic Resonance (NMR) pathological indices and strength in a dose-dependent manner at 3 months post injection (PInj). A recent paper suggested that dystrophin-positive fibers and rAAV genome drastically decrease with time, especially between 3 and 6 months PInj. This may compromise the clinical development of an AAV-mediated gene transfer approach. To assess this point, we realized a 6 to 7 months follow-up in a group of 3 GRMD aged 3–4 months when injected in both forelimbs with 2.5E13 vg/kg of a rAAV8 U7snRNA vector promoting exon skipping. Dogs were injected, followed up and evaluated (NMR, strength assessment, Dystrophin expression, vector biodistribution) in the same way as the previously reported large cohort of dogs that were followed for 3 months. Muscle biopsies were performed at 3 months and complete autopsy at 6 to 7 months PInj. Compared to previously reported dogs injected with the same dose, evaluation of dystrophin expression, histological aspect, AAV genome, NMR parameters and strength showed not differences indicating that the treatment effect was fully maintained over 6 months. No loss in AAV genome quantification and dystrophin expression was observed between the 3 months muscle biopsy specimens and 6 months muscle autopsy in the 3 dogs. A decrement in transgene copy numbers at 6 months PInj was observed in non muscular tissues. These data show, for the first time, that AAV-mediated exon skipping fully maintains dystrophin expression and functional recovery over a six months period. We suggest that long-term rAAV genome stability is obtained in dystrophic muscles when a substantial reversion of the muscular pathological pattern is reached.
Databáze: OpenAIRE
Externí odkaz: