ADVANCES IN MOLECULAR THERAPY RESEARCH ON DYSTROPHIN-DEFICIENT MUSCULAR DYSTROPHY

Abstract

Duchenne muscular dystrophy (DMD) is a lethal muscle disorder caused by mutations of the DMD gene, which encodes a 427-kDa spectrin-like cytoskeletal protein, dystrophin. Exon skipping induced by antisense oligonucleotides is a novel method to restore the reading frame of the mutated DMD gene and rescue dystrophin expression. We recently demonstrated that systemic delivery of antisense phosphorodiamidate morpholino oligonucleotides (PMOs) targeting exons 6 and 8 of the canine DMD gene efficiently recovered functional dystrophin at the sarcolemma of dystrophic dogs, and improved performance of the affected dogs without serious side effects. As a strategy to target hot spots of mutation in the DMD gene, we also tried exon 51-skipping using PMOs in mdx52 mice to convert an out-of-frame mutation into an in-frame mutation with restoration of dystrophin expression in various muscles and improvement of pathology and function. Progress in adeno-associated virus vector serotype 9 (AAV-9)-mediated DMD gene therapy has enabled the delivery of the therapeutic gene to the whole musculature, including cardiac muscle, while evoking minimal immunological reactions in mice, dogs, and non-human primates. Furthermore, DMD-derived patient-specific induced pluripotent stem (iPS) cells could be a potential source for cell therapy, although there are at present hurdles to be overcome. In the future, this technology could be used in combination with exon skipping or AAV-mediated gene therapy to achieve clinical benefits.