A novel strategy to maximize survival of primary and iPS-derived pancreatic islets after transplantation – MAXI-ISLETS

Pancreatic islet transplantation, which entails the intraportal injection of islets sourced from either deceased donors or induced pluripotent stem cells (iPS), provides substantial benefits for individuals with Type 1 Diabetes. However, the low yield of the procedure due to ischemia-reperfusion injuries and inflammatory response limits its therapeutic potential. Our project proposes preconditioning islets with GC7, an eIF5A hypusination inhibitor that has shown anti-ischemic and anti-inflammatory potential, to enhance islet survival and transplantation outcomes. We have obtained promising preliminary data demonstrating that conditioning islets ex-situ with GC7 improves islet survival following exposure to anoxia/reoxygenation in vitro and in vivo in a syngeneic diabetic mouse model of pancreatic islet transplantation. We now aim to assess the potential of GC7 conditioning in preclinical models that closely mimic human conditions, with the goal of providing data robust enough to support a clinical trial by the end of this ANR/DGOS project. Our specific aims include evaluating GC7’s impact in an alloimmune context in a murine islet allograft model; assessing its effectiveness on clinical-grade human primary islets in a humanized diabetic mouse model; and investigating its impact on iPS-derived islets. This project, supported by high-quality preliminary data, could introduce a novel approach to improving islet allograft survival and engraftment, addressing a major current challenge in pancreatic islet transplantation. Simultaneously, it will expand and establish our proficiency in the emerging, groundbreaking field of stem cell-based regenerative therapy for Type 1 Diabetes patients.