Funding opportunities

Prevention of stem cell transplant allorejection through DRAK2 blockade

Funding Type: 
Transplantation Immunology
Grant Number: 
RM1-01738
Funds requested: 
$1 330 476
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
The application of embryonic stem cells (ESC) and derivatives for the treatment a variety of diseases holds much promise. Perhaps such promise is most apparent in recent studies demonstrating efficacy of ESC derivatives in promoting regeneration of nervous tissue damaged during spinal cord injury (SPI). While promising, a significant challenge is that such ESC would necessarily be perceived as “foreign” by our immune system; as is the case with other transplants, these ESC (or ESC derivatives) would be rapidly rejected. Of the variety of cells of the immune system, T cells are essential for preventing opportunistic infections by viruses, bacteria, fungi and other microorganisms. While T cells are clearly necessary for human existence among a broad spectrum of potentially deadly microorganisms, they have the capacity to attack our own tissues, and to promote the rejection of transplants, including ESC and ESC derivatives. Although it is possible to block this transplant rejection using immunosuppressive drugs, lifelong immunosuppression would render ESC recipients highly susceptible to opportunistic infection. Powerful immunosuppressive drugs such as cyclosporine and FK506 are given to transplant recipients to block transplant rejection, but these drugs promotes significant side-effects. Firstly, as described, these transplant patients are highly susceptible to opportunistic infection. Secondly, these drugs promote a variety of “off-target” effects, most notably those that lead to kidney damage and ultimate failure. Clearly, the use of such immunosuppressants would raise quality of life issues for SPI patients, and others receiving ESC therapies. Our laboratory has spent the last decade evaluating a cellular protein called DRAK2 that holds promise for blocking the rejection of transplanted organs and cells such as ESC. DRAK2 is a regulatory protein that is highly expressed in T cells and other cells of the immune system. We have discovered that DRAK2 is required to maintain the survival of T cells under selective circumstances. Most importantly, DRAK2 is required to maintain the survival of T cells that promote graft rejection. Our preliminary experiments have also shown that DRAK2 is necessary for rejection of certain forms of “allografts,” transplants of foreign cells. However, DRAK2 is not required for elimination of micro-organisms such as viruses. In the present CIRM grant application, we address the potential that through blockade of DRAK2, it may be possible to prevent the rejection of ESC allografts. As drugs to inhibit DRAK2 are currently in development, the studies described in this application will allow us to determine if DRAK2 blockade may facilitate ESC transplant survival in an SPI model. These studies will highlight the potential benefits of DRAK2 blockade in treatment of SPI, and more broadly, in preventing rejection of ESC and ESC derivative transplants used in a variety of therapies.
Statement of Benefit to California: 
This program will position California for international competitiveness in this emerging area of biotechnology, as our studies are critical to the clinical development of the two hESC-derivates used in our studies, one of which is within 12 months of being used in human clinical trials, and the second is within 12 months of being presented to the FDA for an IND. Thus, California will benefit from supporting the discovery of what will become the first and second human embryonic stem cell-based clinical trials in the world. This will result in California being a focus of the stem cell industry, including large pharmaceutical companies that will eventually participate in the latter stage stem cell clinical trials. Clinically relevant scientific advances lead to the development of biotechnology companies, creating jobs and taxation. Funding for this proposal will directly create new jobs. In these challenging economic times, we feel that any award should be spent in a manner which enhances the local and state economy, in essence returning direct value to the citizens of California. To this end, we have purposely selected suppliers of equipment and services that are located in the state of California. In addition, due to the booming medical device and biotechnology industries in California, we feel that all new hires can be obtained from within the state of California. Finally, the work described in this application may ultimately be of benefit for other diseases in which transplant tolerance is desired. Such findings could likely lead to the development of new biotech companies to further explore the clinical and commercial potential of DRAK2 blockade.
Review Summary: 
This proposal focuses on the role of DRAK2, a regulatory signaling protein highly expressed in T cells, in the rejection of cellular transplants. The applicant presents preliminary data suggesting that DRAK2 is important for allogeneic immune responses and thus may be a promising target for intervention with drugs designed to promote tolerance to transplanted cells and tissues. The applicant proposes two Specific Aims: (1) to evaluate if DRAK2 signaling plays a role in the rejection of allo- and xenogeneic transplants of neural progenitor cells derived from human embryonic stem cells (hESCs) in an animal model of spinal cord injury (SCI); and (2) to establish the mechanism for allo- and xenograft tolerance induction in T cells lacking DRAK2. Reviewers appreciated the novelty of this proposal, as DRAK2 is not widely studied and represents a potential therapeutic target. They felt that the proposed approach could have an impact if successful in providing evidence that DRAK2 may be worth targeting, but they raised concerns about the project’s maturity and would have been more convinced of the potential for impact if additional preliminary data were presented or a small molecule inhibitor of DRAK2 was available. They also cautioned that focusing on a single molecule in a complex system is rarely successful and noted that DRAK2 is expressed in a variety of cells other than T cells which may be problematic for a therapeutic target. Furthermore, they noted that DRAK2 seems to have contradictory effects on immune activation, raising a concern that perturbing the molecule in clinical application would be unpredictable and risky. The reviewers raised a number of concerns about this proposal’s experimental design and scientific rationale. For example, they did not understand the rationale for transplanting motor neuron progenitors (MNPs) into the animal model of acute SCI. It is not clear how these MNPs will improve function when there is no evidence that they can subsequently innervate their peripheral targets in adult animals. In addition, the transplant experiments are being terminated at 1, 2 or 3 weeks, which reviewers felt was too short a period of time for full cell differentiation to occur. The applicant proposes to follow some animals for longer periods, but no detail is provided on how these animals will be selected. Furthermore, reviewers criticized the proposal’s focus on T cells, since other immune cell types may also play a role in rejection, particularly in the absence of DRAK2. They pointed out that in SCI models, T cells arrive later than macrophages and activated microglia, both of which may play a significant role in early allograft rejection. Reviewers also questioned the behavioral tests proposed to evaluate functional outcomes following SCI. They noted that these tests of paralysis are commonly used in models of a different disease, and that other measures more specific to SCI should be added. Reviewers described the Principal Investigator (PI) as well-established, with an extensive track record in T cell biology and the regulation of tolerance. They appreciated the contributions of the Co-Investigator (Co-I), who brings excellent complementary expertise in neuronal repair, SCI and hESC biology. Reviewers did note that it was difficult to assess the research team as a whole because biosketches were only provided for the PI and Co-I. Nonetheless, they felt the collaboration between these investigators was a strength of the proposal. Overall, while reviewers appreciated the novelty of this proposal, they raised concerns about its experimental design and agreed that it is unlikely to have a major impact on the field.
Conflicts: 

© 2013 California Institute for Regenerative Medicine