Current limitations of gene therapy for rare pediatric diseases: Lessons learned from clinical experience with AAV vectors.

Gene therapy using adeno-associated viral (AAV) vectors is a promising therapeutic strategy for multiple inherited diseases. Following intravenous injection, AAV vectors carrying a copy of the missing gene or the genome-editing machinery reach their target cells and deliver the genetic material. Several clinical trials are currently ongoing and significant success has already been achieved with at least six AAV gene therapy products with market approval in Europe and the United States. Nonetheless, clinical trials and preclinical studies have uncovered several limitations of AAV gene transfer, which need to be addressed in order to improve the safety and enable the treatment of the largest patient population. Limitations include the occurrence of immune-mediated toxicities, the potential loss of correction in the long run, and the development of neutralizing antibodies against AAV vectors preventing re-administration. In this review, we summarize these limitations and discuss the potential technological developments to overcome them. © 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.