CNS targeted AAV gene therapies: Recent advances and clinical insights.

Eight FDA-approved AAV therapies, including four for CNS disorders, show AAV gene transfer can change the course of devastating neurological diseases while key barriers remain.

• Why it matters: Persistent, interdependent challenges—dose-related toxicities, off-target transduction, and the ~4.7 kb packaging limit—must be addressed to expand safe, effective CNS treatment.
• What they did: This review synthesizes AAV biology, capsid engineering, and how administration route and packaging constraints affect safety and efficacy, integrating clinical and postmarketing evidence from CNS and non-CNS uses.
• The result: No single capsid, delivery route, or expression approach fits all CNS disorders; disease-by-disease optimization of capsid, cargo, and administration is required for continued success.

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