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

• Published in: Diabetes (New York, N.Y.) Vol. 73; no. Supplement_1; p. 1
• Main Authors: RECH TONDIN, ARTHUR, YOLCU, ESMA S., HERRING, SARAH K., HESTER, DENNIS M., GADEA, YELENA, VEGA, GREYCY, SZUST, JOEL, REVEL, ARIEL, SHIRWAN, HAVAL, GARCIA, ANDRÉS, JAPOUR, ANTHONY, REVEL, MICHEL, MOLAKANDOV, KFIR, RICORDI, CAMILLO, LANZONI, GIACOMO
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 14.06.2024
• Subjects: Beta cells; Blood glucose; Blood levels; Body weight; Diabetes; Diabetes mellitus; FasL protein; Glucose tolerance; Immunodeficiency; Immunological tolerance; Immunomodulation; Immunomodulators; Immunosuppression; Islet cells; Pancreas; Pancreatic islet transplantation; Peptides; Stem cell transplantation; Stem cells; Streptozocin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db24-2024-LB

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.