Funding opportunities

Genetically engineered immune tolerant human beta cells

Funding Type: 
Tools and Technologies I
Grant Number: 
Funds requested: 
$972 000
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
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.
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. 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.
Review Summary: 
The goal of this proposal is to develop immune-tolerant, human pancreatic beta cells and to test their efficacy and survival in vitro and in vivo. To achieve these ends, the Principal Investigator (PI) will engineer human beta cells that express a particular immune tolerance protein that has been shown to prevent certain cell types from being targeted by the cytotoxic arm of the immune system. The transgenic beta cells will be evaluated for their ability to escape killing by human immune cells in vitro, and for their ability to escape rejection and for functional improvement of metabolism in an in vivo model of diabetes. The reviewers appreciated the premise of this proposal but were discouraged by major weaknesses in the experimental design, mainly due to the investigators’ lack of experience in areas of relevance. The applicants made several false assumptions and chose experimental approaches that were not ideal for this effort. Thus, reviewers questioned the ability of the research team to accomplish the proposed goals. The impact of the proposed technology, in theory, would be tremendous. This approach, if successful, could be beneficial in mitigating autoimmune disease such as Type 1 diabetes and also help in preventing immune rejection in allogeneic stem cell transplantation. However, the reviewers doubted the feasibility of this proposal due to multiple deficiencies in the research plan. They expressed concern about the choice of cells for transduction and considered a major weakness the proposed transduction approach and design considering it unlikely to succeed. They noted that transduction efficiency with a particular vector strategy in one cell type does not necessarily mean similar transduction efficiencies in other cell types. The reviewers noted that the preclinical diabetes model is not fully immunocompetent and is therefore a poor model for testing immunotolerance. In addition, the applicants made several naïve assumptions that may not stand to reason, for example the notion that in vitro immunotolerance would necessarily translate into a lack of immunoreactivity in vivo. Finally, the reviewers noted that the preliminary data was almost all related to identification of the candidate immunosuppressive gene, with nothing directly related to the critical aspects of the proposal such as transduction and expression of cells, nor testing immunosuppressive properties in vitro or in vivo. The reviewers considered the PI well versed in mesenchymal stem cell technology with good knowledge of the immune mediated effects of these cells but lacking in expertise in critical areas of this proposal including beta cell biology. The co-investigators seem to be competent scientists their areas of expertise were also outside of the proposed methodologies. The reviewers uniformly asserted that the applicants would strongly benefit from the addition of a collaborators or consultants in the areas of their weakness. The budget was deemed appropriate, although there was little justification for the details and it seemed heavily weighted towards personnel/salaries. Overall, while the proposed technology could be valuable, the lack of relevant expertise of the research team translated to a proposal that the reviewers believed had a low probability of success.

© 2013 California Institute for Regenerative Medicine