Strategies to improve safety profile of AAV vectors

Adeno-associated virus (AAV) vectors are currently used in four approved gene therapies for Leber congenital amaurosis (Luxturna), spinal muscular atrophy (Zolgensma), aromatic L-amino acid decarboxylase deficiency (Upstaza) and Haemophilia A (Roctavian), with several more being investigated clinical trials. AAV therapy has long been considered extremely safe both the context of immunotoxicity genotoxicity, but recent tragic deaths trials X-linked myotubular myopathy Duchenne’s dystrophy, together increasing reports potential hepatic oncogenicity animal models have prompted re-evaluation how much trust we can place on safety therapy, especially at high doses. In this review cover genome capsid engineering strategies that be to improve next generation immunogenicity genotoxicity discuss gaps need filling our current knowledge about vectors.