Taming immune responses to AAV gene therapy by programmed in vivo Treg expansion

Adeno-associated virus (AAV) vectors are a leading gene therapy vector. However, host recognition of AAV induces cytotoxic T lymphocytes (CTLs) and loss of transgene expression over time. Expanding regulatory T cells (Tregs) could suppress such responses, prevent AAV toxicity, and promote persistence of transgene expression. Interleukin-2 (IL-2) treatment can expand Tregs, but it lacks specificity and durability. THOR-834 is a synthetic PEGylated form of IL-2 engineered for enhanced Treg specificity and with improved half-life. In mice, prophylactic use of THOR-834 expands Tregs, reduces CD8 + effector memory T cells, ameliorates antibody responses against both AAV capsid and transgene product, and enhances productive gene transfer. THOR-834 can also suppress CD8 + T cell responses in a rat model of AAV immunogenicity. In cynomolgus macaques, a single prophylactic dose of THOR-834 expanded Tregs and sustained AAV transgene expression, confirming cross-species efficacy of THOR-834 mediated immunosuppression. These studies represent a novel immunomodulatory strategy that can harness Tregs to enhance the efficacy of gene therapy programs.