Adeno-associated virus for the treatment of muscle diseases: toward clinical trials.

Muscle diseases include muscular dystrophies, cardiomyopathies, neuromuscular and metabolic disorders. The loss of normal muscle structure and function is associated with significant morbidity and mortality. Patients with Duchenne muscular dystrophy usually lose ambulation in their teenage years, and frequently experience severe respiratory problems and heart failure in later stages of life. These unmet medical needs have encouraged the development of genetic strategies targeting the underlying muscle disease processes. Adeno-associated virus (AAV) vectors have been identified as promising gene delivery candidates because of their ability to transduce muscle tissue efficiently while transporting a genetic payload. There is currently significant momentum in the research of AAV-mediated delivery of muscle genes. Various AAV-based therapeutic strategies are undergoing preclinical and clinical testing, including the use of miniaturized and codon-optimized transgenes, exon skipping expression cassettes, novel tissue-specific promoters, AAV capsid mutants and chimeras, and localized intravascular administration procedures. These advancements in gene delivery have led to the generation of AAV vectors with targeted transgene expression, tissue-selective tropism and minimal off-target effects. This review describes advances in AAV gene therapy that are specific to the treatment of muscle diseases, and discusses the implications of their clinical application.