Excluding allogeneic bone marrow transplantation (alloBMT), the treatment of congenital diseases of the stem cell is by definition palliative. The clinical course of patients (pts) with most of these disorders is typified by chronic morbidity secondary to both the pathophysiology of the disorder and the sequelae of available therapy. The goal of this project is the translation of the basic and preclinical studies undertaken in all previous sections as they culminate in clinical experiments designed to correct congenital diseases by utilizing stem cell therapy. Two approaches will be employed which have the common feature of utilization of the totipotent stem cell as a vehicle to produce a missing protein in sufficient quantities to reverse a clinical phenotype. The first approach relies on replacement of the entire hematopoietic system, including the stem cell. Specifically, we propose to extend the availability of alloBMT as a therapeutic option by facilitating the use of haploidentical family members as donors. The second approach is based upon the principle that it may be possible to stably introduce a functional version of a defective gene into the totipotent stem cell. Specifically, we propose to first modify primitive hematopoietic cells of pts ex vivo by transfer of functional genes using viral vectors and then attempt to reconstitute hematopoiesis and normal gene expression and function. To achieve these objectives, we propose two specific aims. First, we plan to undertake clinical trials to demonstrate the feasibility, safety and efficacy of manipulations designed to either anergize or delete donor BM T cells specific for host alloantigen to ameliorate GVHD in pts undergoing haploidentical BMT. In these studies, we plan to immediately enter the clinic attempting to induce anergy to host alloantigen in donor BMT cells in selected pts with congenital diseases eligible for haplomismatched BMT. As preclinical and clinical studies dictate, we will pilot attempts to clonally delete donor T cells specific for host alloantigens in selected pts with hematologic malignancies eligible for haplomismatched BMT and then extend this approach to selected pts with congenital diseases. Second, we plan to undertake a series of pilot clinical studies to establish the feasibility and safety of methodologies which will lead to long term expression of transferred genes in human hematopoietic stem cells. In order to determine whether this manipulation confers stem cell resistance to high dose chemotherapy at the time of relapse, we plan to introduce the MDR-1 gene into the donor BM of pts at high risk for relapse after undergoing 1) alloBMT for hematologic malignancies and 2) autologous BMT for ovarian carcinoma. Ultimately, we will attempt to cure hematopoietic stem cells diseases by gene therapy. The development of these two parallel approaches should yield the most flexibility in eventual triage of therapy for specific pts and disorders. The evolution of these studies is highly dependent on the success of all previous projects.
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