Micro-dystrophin expression as a surrogate endpoint for Duchenne muscular dystrophy clinical trials.

Duchenne muscular dystrophy (DMD) is a serious, rare genetic disease, affecting primarily boys. It is caused by mutations in the DMD gene and is characterized by progressive muscle degeneration that results in loss of function and early death due to respiratory and/or cardiac failure. Although limited treatment options are available, some for only small subsets of the patient population, DMD remains a disease with large unmet medical needs. The adeno-associated virus (AAV) vector is the leading gene delivery system for addressing genetic neuromuscular diseases. Since the gene encoding the full-length dystrophin protein exceeds the packaging capacity of a single AAV vector, gene replacement therapy based on AAV-delivery of shortened yet functional micro-dystrophin genes has emerged as a promising treatment. This paper seeks to explain the rationale for use of the accelerated approval pathway to advance AAV micro-dystrophin gene therapy for DMD. Specifically, we provide support for the use of micro-dystrophin expression as a surrogate endpoint that could be used in clinical trials to support accelerated approval.