AAV-directed muscular dystrophy gene therapy.

IMPORTANCE OF THE FIELD: Muscle-directed gene therapy for genetic muscle diseases can be performed by the recombinant adeno-associated viral (rAAV) vector delivery system to achieve long-term therapeutic gene transfer in all affected muscles. AREAS COVERED IN THIS REVIEW: Recent progress in rAAV-vector-mediated muscle-directed gene transfer and associated techniques for the treatment of muscular dystrophies (MD). The review covers literature from the past 2 - 3 years. WHAT THE READER WILL GAIN: rAAV-directed muscular dystrophy gene therapy can be achieved by mini-dystrophin replacement and exon-skipping strategies. The additional strategies of enhancing muscle regeneration and reducing inflammation in the muscle micro-environment should be useful to optimize therapeutic efficacy. This review compares the merits and shortcomings of different administration methods, promoters and experimental animals that will guide the choice of the appropriate strategy for clinical trials. TAKE HOME MESSAGE: Restoration of muscle histopathology and function has been performed using rAAV systemic gene delivery. In addition, the combination of gene replacement and adjuvant therapies in the future may be beneficial with regard to improving muscle regeneration and decreasing myofiber necrosis. The challenges faced by large animal model studies and in human trials arise from gene transfer efficiency and immune response, which may be overcome by optimizing the rAAV vectors utilized and the administration methods.