Abstract Text: Regulatory T cells (Tregs) drive immunosuppression and are appealing to address unmet therapeutic needs in autoimmune disorders, including type 1 diabetes (T1D). However, sorted cultured Treg cell therapies face difficulties including lack of phenotypic stability, suppressive specificity, expansion, and engraftment support.
GNTI-122 is an autologous engineered Treg therapy for type 1 diabetes designed to overcome these barriers. GNTI-122 is generated from bulk CD4 T cells through CRISPR-Cas knock-in of an MND promoter to stabilize FOXP3, replacement of endogenous TCR with an islet antigen-specific TCR, and insertion of a rapamycin-activated chemically induced IL-2 signaling complex (CISC). This results in phenotypically stable engineered Tregs that target pancreatic islets and expand in subclinical concentrations of rapamycin.
GNTI-122 displays characteristic Treg markers such as CD25, CTLA4, EOS, CD39, CD27, TNFRII, low CD127, low CD70, elevated LAP and GARP expression, and reduced pro-inflammatory cytokines (IL-2, TNF-a, IFNγ). GNTI-122 also demonstrates potent polyclonal and islet antigen-specific suppression in vitro. GNTI-122 uses CISC for pSTAT5 signaling in response to rapamycin alone. This allows rapamycin-dependent rapid expansion, enrichment of edited populations to >90% purity during culture, and tunable engraftment in vivo. Additionally, murine surrogates of GNTI-122 (mEngTregs) preserve beta cell mass after onset of pancreatic inflammation in an adoptive transfer NSG model. mEngTregs specifically traffic to the pancreas where they persist for 9+ weeks and significantly reduce effector memory T cell populations. Collectively, GNTI-122 is an engineered Treg that expresses a stable immunosuppressive phenotype, can be expanded with rapamycin-mediated signaling support, and exerts antigen-specific suppression in mouse models.
