The ability to isolate and expand lymphohematopoietic stem cells (HSC) should improve both the availability and outcome of clinical bone marrow transplantation (BMT). Moreover, clinical transplants with HSC are currently the only way to definitively prove that human HSC have been isolated. Although BMT is curative therapy for most hematologic malignancies and for a variety of fatal non-malignant disorders that effect the lymphohematopoietic system, the majority of patients with these diseases are still not cured. This is, in large part, because patients with these diseases either are not eligible for, or fail, BMT. A graft containing HSC should also be an important method of eliminating (purging) tumor from autologous marrow grafts, especially in those diseases like CML and MDS where it has been difficult to eradicate tumor and simultaneously generate normal hematopoiesis. Transplantation of purified allogeneic HSC should be an important strategy for avoiding histocompatibility problems, graft-versus-host disease (GVHD) and graft rejection, associated with allogeneic BMT. Purified HSC may also be necessary for effective gene transfer therapy for lymphohematopoietic cells, as the rarity of these cells may make them inaccessible to present gene transfer techniques and these techniques may preferentially affect the more rapidly proliferating committed progenitors. The overall objective of this project is to study the use of HSC as treatment for a variety of disease. We will study the use of autologous HSC as treatment of stem failure disorders like MDS, severe aplastic anemia (SAA), and paroxysmal nocturnal hemoglobinuria (PNH). Our preliminary data suggest that the defect in most patients with aplastic anemia and MDS is at the level of a myeloid stem cell rather than the earliest HSC; further, many patients with aplastic anemia and MDS have relatively normal numbers of the earliest HSC. We will also study autologous HSC in the treatment for refractory, life-threatening autoimmune diseases like lupus. Finally, we will utilize isolated allogeneic HSC as a means to overcome histocompatibility problems associated with allogeneic BMT; specifically we will investigate in utero transplantation with allogeneic HSC to treat genetic diseases.
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