Type I diabetes (T1D) is marked by a deficiency of the insulin-secreting beta cells within the pancreas. Because insulin is required for glucose homeostasis, these patients develop high blood glucose, which leads to acute symptoms of frequent urination, unquenchable thirst, weight loss, lethargy and eventually death. The most prevalent method of treatment for T1D is daily injection of recombinant insulin, which increases significantly the long-term survival rate of patients. Unfortunately, insulin injection does not always prevent the extreme glucose excursions experienced by these patients. Therefore, end-stage patients usually develop diabetic kidney diseases and require dialysis, and eventually kidney transplantation. In addition, some patients develop autonomic neuropathy that can lead to dangerous and frequent episodes of hypoglycemic coma, a condition in which people no longer experience the warning symptoms of low blood glucose levels. As a result of these complications, patients become increasingly home-bound and their quality of life is greatly diminished. Transplantation of pancreatic islets from cadaveric donors provides a beneficial cell-replacement therapy for these patients; however, there is an insufficient number of donor organs, which has greatly limited this procedure to a very small number of patients. A possible alternative source of cells for islet transplantation could be developed from human embryonic stem cells (hESCs), which offer a potentially unlimited source of human, pancreatic beta cell-like cells.
In this early translational research proposal, we propose to characterize and enrich a population of glucose-responsive, insulin-producing and secreting (GRIS) cells generated from hESCs in culture that are devoid of inappropriate cell types and of undifferentiated hESCs, which may give rise to tumors when transplanted. We will use a mouse model of diabetes to test the ability of culture-generated, hESC-derived GRIS cells to survive and function in secreting insulin in response to an increase in blood glucose in transplantation recipients. We will also establish a robust assay to detect a small number of undifferentiated hESCs and develop a process to eliminate undifferentiated hESCs before transplantation, should any remain in the final cell preparation. In summary, this project will generate comprehensive efficacy and safety data for our hESC-derived GRIS cells in mouse models of diabetes. Our long-term goals include testing our cellular product in large animal models as the last step before Phase I clinical trials in humans.
Currently, it is estimated that there are more than 1.5 million Americans, including 140,000 Californians with Type 1 diabetes (T1D). Ten to fifteen percent of these patients have advanced forms of the disease and these numbers are expected to rise. Thus, approximately 14,000 to 12,000 Californians could benefit from allogeneic islet transplantation or stem cell-replacement therapy. In addition, it is estimated that a quarter of the Medicare budget is spent on diabetes-related care (including both T1D and T2D), which is a financial burden to State and Federal health care programs, and the taxpayers who support them. The development of a stem cell-replacement therapy for T1D will ease the burden of the long-term, intensive care required for advanced T1D patients.