Genetically engineered immune tolerant human beta cells
Type I diabetes is caused by an immune-mediated process that involves the destruction of one’s own pancreatic insulin producing cells. The mechanisms for this are thought to involve the cytotoxic arm of the immune system. A number of general immunosuppressive medications have been shown to slow down or prevent the onset and/or progression of this autoimmune destruction. However, this benefit always comes at the expense of serious drug-induced side effects. This has led to a need for an immunosuppressive therapy with minimal side effects. Our group has recently discovered a rare subpopulation of mesenchymal stem cells in the fat tissue of humans with persistent immunosuppressive effects. Further studies to characterize the underlying mechanism of immunosuppression revealed these cells block the cytotoxic arm of the immune system by expressing a particular immune tolerance gene. In addition, our preliminary experiments involved transplantation of human cells into mice with a normal immune system. In this model, human cells were not rejected, suggesting that expression of the identified immune tolerance gene may also allow for immune escape across different species. This project proposes to exploit this discovery by creating a special type of insulin producing β cell capable of escaping the expected autoimmune destruction process normally experienced in traditional pancreatic islet cell transplantation procedures. Unlike the current standard of care, our technology would eliminate the need for adjunctive immunosuppression therapy which is normally used to prevent graft rejection of the transplanted β cells. Besides offering a potential cure for type I diabetes, the proposed research holds the potential to create a platform technology that can be used broadly to enable allogeneic cell therapy, thus overcoming one of the major hurdles currently prohibiting stem and somatic cells from realizing their intended clinical promise.
California is home to over 100,000 people suffering from type I diabetes with current demographic trends suggesting this number will steadily increase for the next two decades. Since the onset of type I diabetes is often in childhood, the cumulative impact over a patient's lifetime is significant at a number of levels including quality of life, emotional stability, as well as the currently unavoidable late-stage sequela such as blindness, kidney damage, and cardiovascular disease. The costs associated with providing vigilant monitoring and care for patients with type I diabetes are high and will continue to increase barring a paradigm shift in the therapeutic approach. Much attention has been paid to the treatment of type II diabetes using regenerative medicine approaches such as islet cell transplantation using embryonic stem cells. However, unlike type II diabetes, type I diabetes is caused by an autoimmune reaction against one's own islet cells. Thus, islet cell replacement is unlikely to significantly impact the quality of life of type I diabetics in the absence of preventing the continued autoimmune destruction process. The proposed research aims to develop an innovative therapeutic cell therapy approach that differs from those currently in development. Specifically, the work conducted in this project will allow for the development of a cell based technology that addresses the underlying pathophysiology of type I diabetes by preventing the autoimmune destruction of insulin-producing islet cells. This approach offers the State of California and its citizens a significant advance in the therapeutic approach to type I diabetes, with the potential of curing type I diabetes and permanently restoring sugar control thereby preventing the significant short- and long-term problems associated with this devastating disease. If successful, this approach may be applied more broadly to all autoimmune diseases providing the State of California with the first therapeutic capable of preventing autoimmune disease safely and efficaciously, leading to a tremendous reduction in the California health care burden and improvement in the overall health and productivity of its citizens. Finally, this platform technology has the potential to be applied broadly for all cell therapy applications, thus overcoming one of the major hurdles currently prohibiting stem and somatic cells from realizing their intended clinical promise.