A safety question at the core of AAV gene therapy is drawing new federal attention, as the University of Massachusetts Medical School Worcester has received a USD 1.675 million NIH R01 grant to examine whether manufacturing-associated imperfections in adeno-associated virus vectors raise the risk of host-genome integration.
The University of Massachusetts Medical School Worcester received the four-year award from the National Institute of General Medical Sciences, with the budget period running from May 2026 through April 2030. Principal investigator Phillip W.L. Tai will lead the work, which centers on inverted terminal repeat sequences — the only viral elements retained in recombinant AAV vectors used in gene therapy.
Recent data have indicated that AAV vector DNA integrates into host-cell genomes at higher frequencies than earlier models assumed, and that integrated transgenes contribute meaningfully to long-term expression. Those findings have shifted how the field assesses AAV safety, and this grant is a direct response to that reassessment.
ITR integrity and integration risk
The scientific premise is that truncated or mutated ITRs, which appear in commercially manufactured vectors at measurable frequencies, may influence the likelihood and pattern of genomic integration. Because ITR imperfections observed in manufactured vectors resemble those found at known integration sites, the hypothesis is that vector quality heterogeneity may be a previously underappreciated variable in integration outcomes.
The project is structured around three aims. The first uses next-generation sequencing to characterize ITR structures in wildtype AAV from non-human primate tissues, establishing a baseline for how ITR integrity relates to natural integration behavior. The second tests vectors carrying high proportions of truncated or mutated ITRs against wildtype ITR vectors in cultured human hepatocytes and humanized liver mouse models, using novel cell-culture and NGS-based workflows to track integration. The third examines tissues from non-human primates previously treated with AAV vectors, correlating integration frequency with ITR prevalence across multiple tissue types.