Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman Primates.

Abstract Adeno-associated virus (AAV) vector gene therapy is as a promising treatment for a variety of genetic diseases, including hemophilia. Systemic administration of AAV vectors is associated with a cytotoxic immune response triggered against AAV capsid proteins, which if untreated can result in loss of transgene expression. Immunosuppression (IS) with corticosteroids has limited transgene loss in some AAV gene therapy clinical trials, but was insufficient to prevent loss in other studies. We used a nonhuman primate model to evaluate intensive T cell directed IS combined with AAV-mediated transfer of the human factor IX (FIX) gene. Early administration of rabbit antithymocyte globulin (ATG) concomitant with AAV administration resulted in the development of anti-FIX antibodies while delayed ATG by 5 weeks administration did not. The anti-FIX immune response was associated with increases in inflammatory cytokines as well as a skewed Th17/Treg ratio. We conclude that the timing of T cell directed IS is critical in determining transgene-product immunogenicity or tolerance. These data have implications for systemically administered AAV gene therapy being evaluated for hemophilia A and B as well as other genetic diseases. In nonhuman primates, Samelson-Jones et al. observe that early intensive immunosuppression concomitant with AAV-vector administration enhance the formation of transgene-product antibodies while delaying immunosuppression by 5 weeks does not. This suggests there is a critical time-period when intensive immunosuppression can shift the immune system towards immunogenicity and away from tolerance.