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.