Prevention of stem cell transplant allorejection through DRAK2 blockade
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.
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.