Early Translational I
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.
The goal of this application is to develop a human mesenchymal stem cell (hMSC) technology that could be used as an immunosuppressive therapy to slow or halt the progression of type 1 diabetes (T1D) due to ongoing autoimmune destruction of pancreatic β cells. To this end, the applicants propose to further their hypothesis that the expression of a specific gene, which was previously implicated in conferring transient immune tolerance to MSC cells, can be utilized to overcome the patients’ own immune response and thereby prevent autoimmune destruction of any remaining insulin producing cells. Initial efforts will be directed towards generating transgenic MSC lineages that stably express high levels of the target gene product and demonstrate immune tolerance in vitro. In order to test the efficacy of these tools, a NOD mouse model with a partially humanized immune system will be created. The ability of the engineered cells to prevent the progression of T1D in these hybrid mice will be quantified and compared to that which can be achieved using their unaltered, wild type MSC counterparts. Reviewers agreed that the proposed development candidate addresses an unmet critical need, and that the rationale for halting the progress of type 1 diabetes by preserving a patient’s remaining β cell function is strong. The ability to intervene at early onset, or to specifically target those at high risk for developing this condition, could potentially revolutionize the current standard of care. While the potential impact was appreciated, a number of serious and significant flaws in both the premise and the experimental design cast doubt on the feasibility of this application. First, while it seemed likely that the proposed development candidate could be useful for conferring some level of immune privilege, reviewers were not convinced from the preliminary data that this molecule would be sufficient to overcome all aspects of the immune response. It also seemed unlikely that a specific or localized form of immune protection would result from a general, systemic strategy of nonspecific immunosuppression. Given these uncertainties, the ambitious subsequent investigations were thought to be somewhat premature. Of even greater concern were the described mouse models and efficacy studies, which appeared to be fatally flawed to reviewers. The proposed use of F1 generations were considered naïve, and it appeared that the applicants significantly underestimated the number of crosses, the complexity of analysis, and the lengthier timelines that would be required to derive the appropriate pedigree. Most reviewers agreed that it would require perhaps 10 generations and several years to achieve the appropriate background. A second concern was the absence of evidence to suggest the extent to which the engineered MSCs would escape killing by any component of the mouse adaptive or innate immune system, an important consideration for the subsequent aims in which the efficacy of this potential therapy would be assessed. Finally, reviewers noted some additional challenges that might impede the translation of the proposed technology to the clinic, such as the use of viral vectors and/or other components, as the described therapy would be immunosuppressive and possibly leave the intended patients more vulnerable to potential complications. While an alternative, non-viral transfection strategy was proposed, it appeared doubtful that the appropriate levels of expression and stability would be obtained by this method. In terms of the principal investigator (PI), reviewers felt that, although well published in other areas, the PI does not have a background in immunology and does not demonstrate experience in in vivo mouse genetics or immunobiology. Moreover, reviewers thought that the PI would benefit substantially from collaboration with investigators that are more experienced with cell therapies. One reviewer also found the budget not adequately justified. In summary, reviewers felt that the proposed research addressed a timely and important topic but that the premise was not sufficiently supported by the preliminary data. Of greater concern was the fact that several of the proposed experiments were judged to be unfeasible, improperly designed, and likely beyond the scope of this effort. Finally, reviewers questioned whether certain aspects of the experimental approach might ultimately prove inappropriate for the intended target population and therefore serve as an impediment on the path to translation.