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.