Novel Muscle-Tropic AAV Capsids with Dramatically Enhanced Transduction and Safety Profiles in Non-Human Primates

Abstract

Adeno-associated virus (AAV) gene therapy holds immense promise for treating muscular dystrophies, yet its efficacy and safety are constrained by the suboptimal tissue tropism of natural serotypes. Here, we employed the REACH platform, which combines rational design and directed evolution, to engineer muscle targeting vectors. Systemic administration in non-human primates (NHPs) revealed that lead candidate M1 mediates a >10-fold increase in skeletal muscle transduction compared to the AAV9 and 2-3 fold higher than MyoAAV, while concurrently achieving a remarkable 183-fold reduction in liver distribution. Furthermore, M1 exhibited significant de-targeting from key off-target tissues, including dorsal root ganglia (11 fold), lung (27 fold), spleen (2 fold), and kidney (2 fold). These findings demonstrate that the REACH platform can generate AAV capsids with simultaneously enhanced muscle tropism and favorable safety profiles, addressing a critical bottleneck in muscle-directed gene therapy.