CNS targeted AAV gene therapies: Recent advances and clinical insights

Adeno-associated viral (AAV) vectors are currently the leading platform for in vivo gene transfer to the central nervous system (CNS). Eight FDA-approved AAV therapies, including four for CNS disorders, demonstrate that AAV-based genetic medicines can alter the course of devastating neurological diseases. At the same time, preclinical and clinical experience has identified persistent and interdependent barriers, including dose-dependent toxicities, off-target transduction, and the ∼4.7 kb packaging limit that must be addressed for broader clinical impact and continued success. Here, we review AAV biology and recent capsid engineering strategies, assess how route of administration and packaging constraints impact safety and efficacy, and synthesize clinical and postmarketing data from both CNS and non-CNS AAV gene therapies. We conclude that no single capsid, route of delivery, or expression strategy will address all CNS disorders, and that safe and efficacious treatment will require optimization of capsid, cargo, and administration on a disease-by-disease basis.