I-12. Muscular dystrophy and cardiomyopathy rescue in bio14.6 hamster following single or double aav treatments.

Limb-girdle muscular dystrophies 2C-2D-2E-2F are a distinct subgroup of muscle disorders also known as “sarcoglycanopathies”. They have often a childhood onset and represent among the most severe forms of LGMD, occasionally associated with cardiomyopathy. They result from mutations in any of the four sarcoglycan genes (alpha, beta, gamma, delta) at the dystrophin-associated complex. When one sarcoglycan is absent, the other sarcoglycans are displaced and degraded, since the stability of the complex is impaired. The BIO14.6 hamster is a widely studied model because of its lethal and well- documented course, due to a spontaneous deletion of delta-sarcoglycan gene promoter and first exon. Disease stages are uniform within BIO14.6 strain due to the homogeneous genetic background. The muscle disease is progressive and average lifespan is shortened to 10-13 months, because heart dilation progresses to heart failure. Based on the ability of adeno-associated viral (AAV) vectors to transduce all body muscles following systemic administration, we delivered human delta-sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. We measured the following parameters at different times after the treatment: i) degree and distribution of human delta-sarcoglycan re-expression; ii) re-expression of the other components of the sarcoglycan complex; iii) muscle pathology; iv) cardiac and skeletal muscle function. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis. Motor ability and cardiac functions were completely rescued. Lifespan was extended up to 22 months with sustained delta-SG expression, when we used serotype 2/8 in combination with serotype 2/1.