Résumé :
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Limb-girdle muscular dystrophies 2C-2D-2E-2F (LGMD2C-2F) are classified as "sarcoglycanopathies" and represent the most severe forms, often associated with cardiomyopathy They are caused by mutations in any of the four sarcoglycan (?, ?, ? and ?) genes, expressed at the sarcolemma within the dystrophin-associated complex. The loss of one of the sarcoglycans causes the lack of the others and, consecutively, the disruption of the structure of the muscular fibers. The BIO14.6 hamster is an excellent animal model for its lethal and well-documented course, due to a spontaneous 24kb-deletion of delta-sarcoglycan gene promoter and first exon. We used Adeno Associated Vectors (AAV) to delivery delta-sarcoglycan in cardiomyopathic hamsters, because they are the most promising therapeutic tools for the treatment of muscular distrophies, because of their low immunogenicity and the ability of several serotypes to transduce specifically the cardiac and muscular tissues. We delivered human delta-sarcoglycan cDNA to BIO14.6 hamsters, using intraperitoneal and/or intravenous injections of AAV2/1, AAV2/8 or AAV2/9. We performed also sequential injections, using different serotypes in order to avoid immune response. We made a comparison among different protocols of systemic gene delivery. For each group, we monitored the progression of heart and muscle disease following treatment and the histology of tissues. We observed a body-wide restoration of delta-SG expression, associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis. We observed that muscular and heart functionality completely rescued if gene delivery was performed earlier in life, using AAV2/8 and even more durable with AAV2/8+2/1 sequential injections. The lifespan of treated animals extended up to 22 months with sustained delta-SG expression. Our results show that systemic administration of AAV2/8 alone, or in combination with AAV2/1, is a powerful approach for the therapy of muscular dystrophies.
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