An interesting paper evaluating the challenges faced by the existing generation of AAV vectors and proposing best practices for the future of AAVs in gene therapy. Useful tables of serotype, dose, and outcome are included. [ https://journals.asm.org/doi/10.1128/mbio.02957-25](https://journals.asm.org/doi/10.1128/mbio.02957-25)
Adeno-associated virus (AAV), discovered in 1965 (1), was considered a “biological oddity” and was dubbed as “almost a virus” (2), because it fails to undergo a productive replication in the absence of co-infection with a helper virus, such as adenovirus (3), herpesvirus (4), vaccinia virus (5), or human papillomavirus (6). Infection with the wild-type (WT) AAV infection is also not associated with any known disease in humans. However, following the availability of the complete nucleotide sequence of the WT AAV2 genome (7), molecular cloning (8, 9), and the demonstration of its remarkable ability to integrate site-specifically into human chromosome 19q13.3 (10, 11), sparked a significant interest in AAV, subsequently leading to the development of the first generation of recombinant AAV2 vectors (12, 13), followed by further refinements (14, 15).
Ever since then, interest in AAV vectors has continued to grow exponentially (16–19). The first generation of AAV vectors has been used in at least 700 programs, and there are over 200 currently active Phase I/II/III clinical trials for gene therapy of a wide variety of human diseases. Thus far, seven AAV “drugs”—Luxturna for Leber congenital amaurosis (20–22); Zolgensma for spinal muscular atrophy (23); Hemgenix for hemophilia B (24–27); Elevidys for Duchenne muscular dystrophy (28); Roctavian for hemophilia A (29–32); Beqvez for hemophilia B (33) (Beqvez has now been discontinued); and Kebilidi for aromatic L-amino acid decarboxylase deficiency (34, 35)—have been approved by the US Food and Drug Administration.
