The grant proposes a program of basic and clinical research in stem cell transplantation. Preclinical studies in dogs will develop nonmyeloablative conditioning programs for patients with aplastic anemia, who only require immunosuppression for hematopoietic engraftment, and for patients with genetic diseases, e.g. sickle cell disease, where 20-30% donor-type hematopoiesis may suffice to relieve symptoms. The dog model, which allows for in vivo analysis of stem cell function, will be used to define the limits of cord blood transplantation, with emphasis on in vitro expansion that is needed to increase cell yield for transplantation into adults and for gene therapy. Additional studies will focus on improved retroviral delivery systems for gene therapy, to improve upon clinical gene therapy studies already begun in patients with Gaucher's disease. Clinical studies will address ways of increasing the application and efficacy of stem cell transplantation for treating aplastic anemia (AA), myelodysplastic syndromes (MDS), and autoimmune disease, as well as genetic diseases, in conjunction with these projects, in vitro studies of cellular interactions will define how diseased cells in MDS or AA may be capable of suppressing normal hematopoiesis, possibly leading to alternative forms of therapy for these diseases as well as other marrow failure syndromes. Marrow grafts from HLA-identical siblings will be continued with emphasis on developing new regimens for preventing graft rejection and acute GVHD. Efforts to increase the number of patients eligible for transplantation will focus on the use of less well matched family members and of unrelated individuals as donors. As more patients become long-term survivors, long- term follow-up studies have become imperative to understand, treat, and prevent secondary malignancies and chronic GVHD. All of the clinical and laboratory studies are supported by core components which provide sample acquisition and analysis, as well as study design, data processing, and statistical analyses. Other cores deal with the outpatient department and grant administration. The principles derived from the proposed studies will make it possible to provide more effective treatment to a greater number of patients.
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