Development of an immune evasive stem cell line for Type 1 diabetes regenerative therapy

PROJECT SUMMARY Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the destruction of insulin-producing β-cells within pancreatic islets, culminating in dysregulated blood glucose levels, affecting 2 million Americans. The standard of care for T1DM is continuous glucose monitoring and exogenous insulin therapy. Despite significant advancements in insulin delivery methods, only 17% of children and 21% of adults achieve the recommended HbA1c levels of <7.5 and 7%, respectively. Clinical islet transplantation (CIT), during which allogeneic donor islets are injected into the portal vein, has successfully obtained 78% insulin independence; however, CIT is challenged by allogeneic human cadaveric islet supply, graft failure, and the need for chronic immunosuppression. Implantation of cadaver islets or stem cell-derived islets (SC-Islets) either unencapsulated or surrounded by a semipermeable encapsulating membrane designed to be immune-protective is also being explored but requires immunosuppression or presents the risk of fibrosis, respectively. None of the current treatments have replicated native β-cell function; therefore, there is a critical unmet need for more efficacious T1DM treatments. Thus, Aleutian Therapeutics (Aleutian) is developing a novel cell therapy that addresses the limitations of available treatment options for T1DM. Aleutian’s innovative novel technology involves the generation of allogeneic islet-like organoids from pluripotent stem cells and gene modification to enable immune evasion upon transplantation. Together, these innovations will alleviate the cell supply limitation and the requirement for immune suppression treatment of current cell therapies. Aleutian’s academic collaborator has previously conducted animal studies demonstrating: 1) the successful differentiation of stem cells into islet-like organoids and glycemic control upon transplantation; and 2) the extension of cell survival following the introduction of programmed cell death ligand 1, a known regulator of immune tolerance, in an immune-competent xeno mouse model. However, these cells do not survive in the mice long-term due to xeno and allo immune rejection. Aleutian therefore plans to develop a panel of edits targeting broad innate and adaptive immune compartments. The goal of this Phase I study will be to show in vitro proof-of-concept of immune evasion with these edits and the ability to differentiate into allogeneic islet-like organoids. We aim to produce and bank the gene-edited cell lines and subsequently evaluate them for SC-Islet differentiation, in vitro function, and immune evasion in vitro. Successful completion of the proposed Phase I study will show that engineered stem cell-derived islet-like organoids are capable of glucose-stimulated insulin secretion while evading immune reactivity in vitro, which will inform Phase II in vivo efficacy studies.