Comparative in vivo characterization of newly discovered myotropic adeno-associated vectors

Abstract Background Adeno-associated virus (AAV)-based gene therapy is a promising strategy to cure muscle diseases. However, this strategy is currently confronted with challenges, including a lack of transduction efficiency across the entire muscular system and toxicity resulting from off-target tissue effects. Recently, novel myotropic AAVs named MyoAAVs and AAVMYOs have been discovered using a directed evolution approach, all separately demonstrating enhanced muscle transduction efficiency and liver de-targeting effects. However, these newly discovered AAV variants have not yet been compared. Methods In this study, we performed a comparative analysis of these various AAV9-derived vectors under the same experimental conditions following different injection time points in two distinct mouse strains. Results We highlighted MyoAAV2A as the best candidate for leg muscle and heart transduction and AAVMYO for diaphragm transduction and liver de-targeting. Of note, these efficiencies were found to depend both on age at injection and mouse genetic background. Conclusions Our study provides guidance for researchers aiming to establish proof-of-concept approaches for preventive or curative perspectives in mouse models, to ultimately lead to future clinical trials for muscle disorders.