Type 1 diabetes (T1D) is a chronic disease that destroys insulin-producing beta cells in the pancreas, leading to long-term complications that include kidney failure and blindness. Islet cell transplantation in the liver has emerged as a promising therapy for T1D, but the potential success of this approach is hampered by issues with islet shortage and a gradual loss of islet graft function in the inhospitable liver environment. The long-term goal of our team is to advance cell-replacement therapy as a durable cure for T1D by first developing a renewable source of cells that secrete insulin in response to glucose like native pancreatic islets, and then developing a safe and strategic approach for their transplantation in patients, which will feature an alternative, non-liver transplantation site under the skin. Our primary objective for this proposal is to advance our therapeutic development candidate, glucose-responsive, insulin-secreting (GRIS) cells derived from human embryonic stem cells, to the preclinical studies necessary to support IND filing with the FDA, which will enable us to determine the safety, feasibility, and efficacy of this product in humans as a cell-replacement therapy for T1D. Because the main safety concern with stem cells is the risk for tumor formation, we have already developed methodology: to purify GRIS cells prior to transplantation in order to remove potentially harmful undifferentiated cells from the preparation; evaluate the purified GRIS cells for quality, function, and viability using our previously established, advanced islet quality assessment methodologies; and to determine the minimum effective number of cells required to reverse diabetes in a patient. We have also already obtained a biocompatible, degradable hydrogel material on which we will suspend the GRIS-cell graft in order to: reduce crowding and death of the GRIS cells; enhance their function and survival by promoting the growth of new blood vessels (vascularization) to support the graft; limit their migration; and facilitate the retrieval of the graft after transplant, if necessary, which greatly enhances the safety of our product. We will also test whether co-transplantation with mesenchymal stem cells derived from a patient’s own fat tissues will further enhance the survival and function of transplanted GRIS cells by promoting vascularization and preventing immune attack by creating a protective, immune-privileged environment, and we will treat the hydrogel with growth factors to encourage additional graft vascularization. A canine islet transplantation model will be used to validate the transplantation techniques described above. Finally, we will confirm the feasibility, safety, and efficacy of our final cell product and transplantation approach as determined through this series of preclinical studies as a cell-replacement therapy for human use by filing an IND application with the FDA to initiate a Phase I clinical study.
Statement of Benefit to California:
It is estimated that there are more than 1.5 million Americans with type 1 diabetes (T1D). Of these, approximately 140,000 patients are Californians, and 10-15% of these patients already have advanced forms of the disease (e.g., kidney failure). Without intervention and based on current incidence data (~40,000 new cases per year), these numbers are expected to rise substantially over the next 20 years. Cadaveric islet transplantation has emerged as a promising treatment for T1D, but islet shortage remains a significant obstacle to the widespread application of this approach. About 270 cadaveric pancreata become available per year in the entire southwestern region of the United States (CA, AZ, NV, NM), but because many of the resulting islet isolations are deemed unsuitable for clinical use, in addition to the fact that an average of two donor pancreata is required to treat a single T1D patient, it is only possible to transplant fewer than 100 patients annually. Thus, at best, we are not able to treat >99% of the most critical T1D patients in California. The generation of a safe, abundant, and renewable source of glucose-responsive, insulin-producing cells derived from human embryonic stem cells represents an ideal, innovative strategy that will help to meet the needs of T1D patients in California and provide them with significant benefits in terms of freedom from insulin injections and improved quality of life as the result of better blood glucose control.