TRANSLATIONAL STRATEGIES FOR PANCREATIC ISLET XENOTRANSPLANTATION IN NHP

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent advances in human allogeneic islet transplantation have established the proof-of-concept for beta cell replacement therapy and suggest this approach could emerge as a treatment option for type 1 diabetes. However, the number of human islets available for transplantation continues to limit clinical research and therapeutic application. Alternative sources of islets are being pursued to address this problem. These include recovery of islets from living donors, genetically engineering insulin-secreting cells, in vitro expansion of beta-cells, differentiation of stem cells or pancreatic precursor cells into beta-cells, and preparation of islets from xenogeneic sources. This study addresses the possibility of clinical porcine islet cell transplantation. Recent data indicates the need for research with non-human primate models to make decisions regarding the design of clinical trials in humans. The goal of this project is to provide information needed to design a clinical trial involving neonatal porcine islets. The priority areas addressed will be: 1) Determination of the optimal islet mass of neonatal porcine islets required to correct diabetes in a non-human primate transplant model using a costimulation blockade-based immunosuppression regimen; 2) Determination of the optimal site of implantation of the optimized mass of neonatal porcine islets ; 3) Obtaining adequate long-term efficacy, safety, and immunological data in a non-human primate model to support an IND for a clinical trial using neonatal porcine xenografts. We have had reduced success with engraftment of neonatal porcine islets following streptozotocin treatment, but have identified a number of controllable factors that may have contributed to this decreased efficacy. We have achieved long-term success with allogeneic islet transplantation following streptozotocin-induced diabetes using costimulatory blockade immunosuppression, and we expect to identify the requirements of this regimen to achieve similar success with xenogeneic islets. Additional work will be done to establish the optimum drug regimen for immunosuppression in the xenotransplantation model.