Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle

Abstract

Gene therapy vectors based on adeno-associated virus tend to accumulate in the liver, limiting their utility for targeting other organs. Using site-directed mutagenesis of the capsid surface, Asokan et al. generate a variant that efficiently transduces a wide range of muscle groups while avoiding the liver. Reengineering the receptor footprints of adeno-associated virus (AAV) isolates may yield variants with improved properties for clinical applications. We generated a panel of synthetic AAV2 vectors by replacing a hexapeptide sequence in a previously identified heparan sulfate receptor footprint with corresponding residues from other AAV strains. This approach yielded several chimeric capsids displaying systemic tropism after intravenous administration in mice. Of particular interest, an AAV2/AAV8 chimera designated AAV2i8 displayed an altered antigenic profile, readily traversed the blood vasculature, and selectively transduced cardiac and whole-body skeletal muscle tissues with high efficiency. Unlike other AAV serotypes, which are preferentially sequestered in the liver, AAV2i8 showed markedly reduced hepatic tropism. These features of AAV2i8 suggest that it is well suited to translational studies in gene therapy of musculoskeletal disorders.