A Translational Pathway Toward a Clinical Trial Using the Second-Generation AAV Micro-Dystrophin Vector

Duchenne muscular dystrophy (DMD) can be caused by thousands of different mutations in the dystrophin gene. Replacing the mutated gene with a functional microgene offers a one-size-fits-all therapy. Several dozens of first-generation microgenes have been shown to reduce muscle disease in mdx mice. However, early attempts in DMD dogs and human patients have failed to reproduce the success in mice. We have recently discovered the dystrophin domain responsible for restoring neuronal nitric oxide synthase (nNOS).Failure to restore nNOS significantly contributes to the initiation and progression of DMD. DMD affects all muscles in the body. An effective therapy for DMD requires bodywide therapy. While studies performed in the mouse models have been encouraging, they are poorly translated to patients. Testing systemic microgene therapy in the symptomatic dystrophic dog model is absolutely required to establish the premise for a clinical trial. In this study, we demonstrated effective bodywide systemic AAV microgene therapy in the canine DMD model. Our findings have provided the foundation for the recent initiation of human trials.