Given their practically, unlimited availability and capabilities to produce every organ in the body, embryonic stem cells are well poised as a cellular source for tissue regeneration therapy. However, it has been shown that ES cells are rejected by the recipient's immune system and that any future use of ESC is likely to require the use of systemic medications to overcome the rejection of these grafts. These treatments are usually quite toxic and result in significant morbidity and mortality.
We have developed a novel and practical model of bone marrow transplantation to induce tolerance to graft from different genetic backgrounds of the recipient. Unlike the usual bone marrow transplantation protocols, this is a non-toxic and therefore well tolerated regimen that requires no long term treatment with anti-rejection drugs. In this model, blood cells developed from hematopoietic stem cells will be used as a means to induce a tolerance to future grafts made from the same embryonic stem cells for regenerative purposes.
While the focus of this grant will be on induction of tolerance to grafts made from embryonic stem cells, the application of this approach can quickly spread for therapies for a wide variety of other disorders. Examples of such an applications are the treatment of blood cancers, as a part of immunotherapy for solid tumors, to prevent rejection of adult grafts such as kidney or heart transplant, the treatment of autoimmune disorders such as severe cases of arthritis and treatment of a wide variety of hereditary disorders such as thalassemia and sickle cell diseases.
Statement of Benefit to California:
While the potential clinical application of embryonic stem (ES) cells and their derivatives are expanding, there has been very little focus on the immunological aspects of their use. There is a very high chance that ES derived tissues are easily rejected by the host without aggressive immunosuppressive medications. On the other hand, the side effects of immunosuppressive drugs are, in most cases, overwhelming for the patients and result in significant morbidity and even mortality for these patients. The widespread clinical application of any ES cell related therapeutic approach will rely on overcoming the problems associated with graft rejection.
The use of induced pluripotent stem cells (iPS cells) will be limited at this point due to issues with gene therapy. This is specifically a bigger problem in the case of hereditary disorders and malignancies when permanent cloning of the cells is needed. Furthermore, it is not clear if autologous iPS cells from the older patients, the target of most of the regenerative medicine protocols, has the same pluripotency and safety profile of already established ES cells.
We believe that by inducing low levels of stable mixed hematopoietic chimerism from ES derived hematopoietic stem cells using a non-toxic transplant model, we will achieve long term tolerance to the graft and therefore prevent its rejection.
More importantly, the clinical application of this approach is not limited to the induction of tolerance to the ES derived organs. Induction of stable mixed chimerism can be used in a wide spectrum of clinical applications including but not limited to treatment of hematological malignancies, induction of tolerance to the allogeneic immune reactive cells as a part of immunotherapy for solid tumors, induction of tolerance for solid organ transplants, treatment of autoimmune disorders and treatment of a wide variety of hereditary disorders such as sickle cell anemia and thalassemias. Each of these clinical scenarios currently create significant clinical problems for the patients as well as a significant financial burden on the California Budget.