Directed evolution of liver-detargeted AAV vectors for systemic gene delivery to skeletal muscle and heart.

ABSTRACT: Adeno-associated virus (AAV) gene therapies that require systemic administration of high vector doses are associated with hepatotoxicity risk, given the liver tropism of most AAV vectors. We combined screening of natural serotypes, targeted mutagenesis, and directed evolution to identify liver-detargeted muscle-tropic capsids. We found that AAVhu.32 is liver-detargeted compared to AAV9, and AAV5 exhibits high skeletal muscle biodistribution albeit with low transgene expression. Following two rounds of peptide insertion library-based directed evolution of AAV9.AAA (a previously described variant) and AAV5, we identified peptides NVG7 and NVG13, respectively, that confer increased muscle transduction compared to the base capsid with liver-detargeting compared to AAV9 in mouse. In non-human p

SUBMITTER: Firnberg E 

PROVIDER: S-EPMC12451274 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature