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 used to slow down or prevent the onset and/or progression of this autoimmune destruction. However, these treatments have been met with limited success due to serious end-organ toxicity and other side effects. To date, there are unfortunately no FDA-approved therapies for the prevention of type I diabetes progression. This has led to a need for an immunosuppressive therapy with minimal side effects. Although no approved treatments exist, recent preclinical studies suggest mesenchymal stem cells (MSCs) possess immunosuppressive effects capable of delaying the progression of type I disease. While clearly exciting, several challenges must be overcome in order to fully realize the potential of MSCs as recent evidence suggests the immunosuppressive effect is only transient and lost within weeks of transplantation. Our lab has recently discovered a rare subpopulation of MSCs in the fat tissue of humans with more persistent immunosuppressive effects. Further studies to characterize the underlying mechanism of immunosuppression revealed that 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 expressing this gene into mice with a normal immune system. In this model, these 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 MSC with persistent immunosuppressive effects. This modified MSC will be used to halt the autoimmune destruction process in type I diabetic patients, thus preserving their own insulin-producing β cells. If successful, our technology would eliminate the need for insulin replacement therapy and permanently restore euglycemia. The proposed research also holds the potential to create a platform technology that can be used broadly to enable allogeneic cell therapy, helping overcome the immune mismatch barrier currently prohibiting stem and somatic cells from realizing their intended clinical promise.
Statement of Benefit to California:
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. Thus far, treatments have focused on replacing insulin with no current FDA-approved treatments on the market for prevention of type I diabetes progression. The aim of this project is to complete the early translational research for a development candidate for the prevention of type I diabetes progression due to ongoing autoimmune destruction of insulin-producing pancreatic β cells. In order to accomplish this, our proprietary cell therapy would be administered shortly after the initial diagnosis is made, halting type I diabetes progression and and permanently restoring sugar control thereby preventing the significant short- and long-term problems associated with this devastating disease. This approach offers the State of California and its citizens a significant advance in the therapeutic approach to type I diabetes, leading to a tremendous reduction in the California health care burden and improvement in the overall productivity of its citizens. If successful, this approach may be applied more broadly to all autoimmune diseases providing the State of California with the first stem cell therapeutic capable of preventing autoimmune disease safely and efficaciously, Finally, this platform technology has the potential to be applied broadly for all cell therapy applications, thus overcoming the immune mismatch barrier currently prohibiting stem and somatic cells from realizing their hoped for clinical promise.