Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector

Limb-girdle muscular dystrophies 2C-F represent a family of autosomal reces sive diseases caused by defects in sarcoglycan genes'. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy c aused by a primary deficiency in delta-sarcoglycan(2-5). We show here that acute sarcolemmal disruption occurs in this animal model during forceful mu scle contraction. A recombinant adeno-associated virus vector encoding huma n delta-sarcoglycan conferred efficient and stable genetic reconstitution i n the adult cardiomyopathic hamster when injected directly into muscle. A q uantitative assay demonstrated that vector-transduced muscle fibers are sta bly protected from sarcolemmal disruption; there was no associated inflamma tion or immunologic response to the vector-encoded protein. Efficient gene transduction with rescue of the sarcoglycan complex in muscle fibers of the distal hindlimb was also obtained after infusion of recombinant adeno-asso ciated virus into the femoral artery in conjunction with histamine-induced endothelial permeabilization. This study provides a strong rationale for th e development of gene therapy for limb-girdle muscular dystrophy.