Immune Modulation via Expansion of Treg Cells By THOR-834 Leads to Enhanced rAAV Transgene Expression 9042

Description Gene therapy using recombinant adeno-associated viral (rAAV) vectors is a promising approach for treatment of variety of genetic disorders. Host adaptive immune responses can generate cytotoxic T lymphocytes (CTL) and as reported in some clinical trials, loss of transgene expression over time. Our goal was to exploit the suppressive capacity of Regulatory T cells (Tregs) to control such CTL responses, avoid potential AAV toxicity, and promote persistence of transgene expression. Interleukin-2 (IL-2) treatment activates Tregs, however, IL-2 is not specific to Tregs and is rapidly cleared. THOR-834 is a synthetic PEGylated form of IL-2 with enhanced Treg specificity and a longer half-life. We hypothesized that THOR-834 could promote expansion of Tregs, thus minimizing AAV-mediated CTL responses. We treated mice with THOR-834 alongside rAAV and observed expansion of Tregs, reduction of effector memory CD8 T cells, and enhancement of transgene levels. THOR-834 treatment in a rat model of DRG toxicity also exhibited suppression of CD8 T cell responses. Finally, in cynomolgus macaques, treatment with a single dose of THOR-834 led to Treg expansion and enhanced transgene levels following rAAV gene delivery thereby confirming that THOR-834 dampened rAAV-mediated immune responses in non-human primates as well. These studies lay the groundwork for a new strategy which harnesses Tregs to suppress adaptive immune responses to AAV and enhance the efficacy of rAAV-based gene therapy.