The overall goal of this SCOR proposal is to develop clinical translational strategies to correct congenital diseases of the human hematopoietic stem cell. Recognizing that the diversity of pathophysiologies and clinical circumstances are likely to require more than one therapeutic approach, we have elected to undertake concurrent basic scientific and clinical translational studies in two arenas. The first approach will focus upon global replacement of the hematopoietic stem cell by haploidentical allogeneic bone marrow transplantation. To achieve this goal, Projects 4, 5 and 6 will attempt to reduce or ameliorate the incidence and complications of graft vs host disease by attempting to anergize or clonally delete host alloreactive T cells present in haploidentical donor bone marrow. These studies will span basic laboratory investigations, murine and human preclinical studies, and human experimentation. If successful, haploidentical allogenic bone marrow transplantation could provide a readily available source of donor bone marrow for most patients with congenital diseases of the hematopoietic stem cell. The second approach will focus upon developing strategies to safely, efficiently, and effectively correct congenital diseases of the hematopoietic stem cell by gene transfer into stem cells. To achieve this goal, Projects 1, 2, 3 and 5 will determine optimal methods to isolate and potentially expand stem cells, establish conditions which optimize gene transfer into stem cells, determine the optimal methodologies to transfer genes into autologous stem cells, test in vitro methodologies in murine preclinical methods to evaluate both efficacy of gene transfer and optimal conditioning regimens for autologous stem cell engraftment and correct congenital diseases of the stem cell in murine models. Finally, these studies will provide methodologies to correct one or more congenital diseases of the human hematopoietic stem cell and will provide the technology to proceed to gene transfer studies of more complex acquired or congenital disorders. The strength of this proposal lies in its focused drive toward clinical experimentation. By electing to attempt two distinct, yet potentially efficacious strategies, we will be in clinical experimentation by year 1 and, without question, will be able to evaluate the relative merits of these approaches by the completion of this project. This SCOR has been highly interactive in its genesis. To insure its success, we have assembled a highly diverse yet interactive collaborative team of molecular and cell biologists, immunologists, transplant biologists, hematologists, and clinicians with extensive translational experience to accomplish these goals.
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