Capsid-Engineering for Central Nervous System-Directed Gene Therapy with Adeno-Associated Virus Vectors

Closing the gap in knowledge on the cause of neurodegenerative disorders is paving the way toward innovative treatment strategies, among which gene therapy has emerged as a top candidate. Both conventional gene therapy and genome editing approaches are being developed, and a great number of human clinical trials are ongoing. Already 2 years ago, the first gene therapy for a neurodegenerative disease, spinal muscular atrophy type 1 (SMA1), obtained market approval. To realize such innovative strategies, gene therapy delivery tools are key assets. Here, we focus on recombinant adeno-associated virus (AAV) vectors and report on strategies to improve first-generation vectors. Current efforts focus on the viral capsid to modify the host–vector interaction aiming at increasing the efficacy of target cell transduction, at simplifying vector administration, and at reducing the risk of vector dose-related side effects.