Marc Bartoli, Carinne Roudaut, Samia Martin, Franc¸oise Fougerousse, Laurence Suel,
Je´roˆme Poupiot, Evelyne Gicquel, Fanny Noulet, Olivier Danos, and Isabelle Richard
Mol Ther. 2006 Feb;13(2):250-9. Epub 2005 Nov 14
Safety and Efficacy of AAV-Mediated Calpain 3Gene Transfer in a Mouse Model of Limb-Girdle Muscular Dystrophy Type 2A
Calpainopathy (limb-girdle muscular dystrophy type 2A, LGMD2A) is a recessive muscular disorder caused by deficiency in the calcium-dependent cysteine protease calpain 3. To date, no treatment exists for this disease. We evaluated the potential of recombinant adeno-associated virus (rAAV)vectors for gene therapy in a murine model for LGMD2A. To drive the expression of calpain 3, weused rAAV2/1 pseudotyped vectors and muscle-specific promoters to avoid calpain 3 cell toxicity. We report efficient and stable transgene expression in muscle with restoration of the proteolytic activity and without evident toxicity. In addition, calpain 3 was correctly targeted to the sarcomere. Moreover, its presence resulted in improvement of the histological features and in therapeuticefficacy at the physiological levels, including correction of atrophy and full rescue of the contractile force deficits. Our results establish the feasibility of AAV-mediated calpain 3 gene transfer as a
therapeutic approach.