Directed evolution of novel AAV capsids for enhanced delivery to mouse and human Schwann cells

Effective delivery to target cell types remains a major obstacle for gene therapy. Recombinant adeno-associated viruses (AAVs) have proven to be effective delivery vectors for the treatment of several diseases yet still have to demonstrate efficient delivery to many cell types, including cells of the peripheral nervous system. Schwann cells-essential for myelination, nerve regeneration, and general nerve maintenance-are strategic gene therapy targets for treating peripheral neuropathies but present unique challenges for gene delivery due to their protective barriers and diffuse localization throughout the body. To address this issue, we engineered novel AAV variants with enhanced transduction efficiency toward Schwann cells. Using directed evolution, we identified two groups of capsids with significantly improved delivery to these cells in mice or human. In addition to higher transduction efficiencies, human-tropic capsids also demonstrated higher resistance to antibody neutralization compared to natural serotypes. In vivo studies of mouse-tropic capsids confirmed higher selectivity, improved packaging titers, and decreased localization to the liver. These engineered AAVs are valuable tools for studying Schwann cells and offer new avenues for the treatment of peripheral nerve disorders.