Development of new therapy on muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked, lethal disorder caused by a defect in the DMD gene. We have previously reported that micro-dystrophins, which have large deletions in rod repeat domain, successfully localize at the sarcolemma and stabilize dystroglycan-sarcoglycan complex in dystrophin-deficient mdx muscle. However, expression of a 3.7-kb micro-dystrophin cDNA, having only one rod repeat showed no effect on dystrophic phenotype. Further transgenic experiments are carrying to seek a functional but small-sized micro-dystrophin cDNA, which can be accommodated into Adeno-associated virus (AAV) vector. In normal muscle, AAV-LacZ vector expresses stably beta-gal for a long period, however, we noticed that immune response is evoked by AAV-LacZ vector in mdx muscle. Therefore, for successful gene therapy, it is required to reduce immune response against AAV-dystrophin vector and therapeutic proteins in mdx mice. We have already reported that utrophin was up-regulated at the sarcolemma of mdx mice, when a beta-galactosidase-expressing adenovirus vector, AxCALacZ was injected into the skeletal muscle. Moreover, up-regulated utrophin mitigated dystrophic phenotypes. Up-regulation of utrophin was induced by inflammatory response against adenovirus vector-mediated gene transfer and this up-regulation is one of promising tools for treatment of DMD.