2024-LB: Reversal of Diabetes by Human Stem Cell–Derived Islets Implanted with an Immunomodulatory Microgel in a Retrievable Site

Introduction & Objective: Islet transplantation for T1D is limited by donor availability and need for immunosuppression. Stem cell-derived islets could represent a solution as an unlimited source, but chronic immunosuppression remains a critical barrier. Immunomodulatory SA-FasL engineered microgel (iTOL-100, iTolerance Inc) represents a viable option to eliminate chronic immunosuppression. This study aimed to investigate the effect of human stem cell-derived islets (IsletRx, Kadimastem Ltd) co-transplanted with SA-FasL microgel in streptozotocin-diabetic immunodeficient NSG mice, to assess potential clinical translation. Methods: IsletRx cell clusters were shipped via intercontinental flight. IsletRx was implanted in the epidydimal fat pad at doses from 3 to 9 kIEQ per mouse, alone or with iTOL-100. Over three months of follow-up, animal body weight and glycemia were monitored to assess transplantation effects. Human C-peptide levels were periodically measured and Intraperitoneal Glucose Tolerance Tests (IPGTT) performed. Results: The study demonstrated that IsletRx engrafted, resulting in substantial human C-peptide release and normalization of blood glucose levels. At the highest IsletRx dose (9 kIEQ, approximately 5 million cells), glycemic control improved over 3 months, reaching euglycemia. Importantly, iTOL-100 did not adversely affect stem cell-derived IsletRx function. Histological analyses of the grafts revealed well-preserved stem cell-derived islets. Conclusion: The results indicate the potential of IsletRx as a stem cell-derived islet candidate for the treatment of subjects with T1D. Notably, IsletRx can be shipped intercontinentally, and thus could be delivered worldwide as a functionally competent clinical product. Additionally, our findings indicate that the combination of stem cell-derived IsletRx with the immunomodulatory iTOL-100 microgel does not compromise beta cell function and reversal of diabetes.