rAAV vector-mediated sarcoglycan gene transfer in a hamster model for limbgirdle muscular dystrophy

The limb girdle muscular dystrophies (LGMD) are a genetically and phenotypi cally heterogeneous group of degenerative neuromuscular diseases. A subset of the genetically recessive forms of LGMD are caused by mutations in the f our muscle sarcoglycan genes (alpha, beta, gamma and delta). The coding seq uences of all known sarcoglycan genes are smaller than 2 kb, and thus can b e readily packaged in recombinant adeno-associated virus (rAAV) vectors. Pr eviously, we have demonstrated highly efficient and sustained transduction in mature muscle tissue of immunocompetent animals with rAAV vectors, in th is report, we utilize recombinant AAV containing the delta-sarcoglycan gene for genetic complementation of muscle diseases using a delta-sarcoglycan-d eficient hamster model (Bio14.6). We show efficient delivery and widespread expression of delta-sarcoglycan after a single intramuscular injection. Im portantly, rAAV vector containing the human delta-sarcoglycan cDNA restored secondary biochemical deficiencies, with correct localization of other sar coglycan proteins to the muscle fiber membrane. Interestingly, restoration of alpha-, as well as beta-sarcoglycan was homogeneous and properly localiz ed throughout transduced muscle. and appeared unaffected by dramatic overex pression of delta-sarcoglycan in the cytoplasm of some myofibers. These res ults support the feasibility of rAAV vector's application to treat LGMD by means of direct in vivo gene transfer.