) Current allogeneic hematopoietic stem cell transplant regimens for the treatment of inherited diseases consist of three parts. The first is a conditioning program of high dose busulfan and cyclophosphamide which aims to eradicate the underlying disease and to suppress host-versus-graft (HVG) reactions. The second is the stem cell graft whose role is to rescue the patient from the otherwise lethal marrow toxicity of the conditioning program and to replace the diseased marrow. The third is postgrafting immunosuppression to prevent graft-versus-host disease (GVHD). A major problem with the current approach has been significant morbidity and mortality from the myeloablative conditioning regimens. Based on results in experimental dogs (see Project 1 ), the development of a novel approach for the allografting of inherited red blood cell diseases is proposed that is less toxic and can safely be administered in an ambulatory care clinic. The transplant regimens will not be myeloablative but primarily immunosuppressive with the aim of controlling both HVG and GVH reactions. The hypothesis, to be tested first in the dog model, is that mixed hematopoietic chimerism can cure the phenotypic expression of inherited red blood cell diseases. This requires the demonstration of both stable engraftation and sufficient improvement of the hematologic abnormalities to correct the clinical manifestations including those related to iron overload. Mixed chimerism will be induced with 200 cGy of total body irradiation (TBI), transplantation with DLA-identical marrow, and postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). The combination of MMF/CSP after transplantation to suppress HVG reactions is central to the success of less intense conditioning regimens. One of the two evaluable dogs with chronic hemolytic anemia secondary to pyruvate kinase deficiency has had stable mixed chimerism for 4 months with correction of the hematologic abnormalities. If successful, this work will provide the rationale for future clinical trials in patients with sickle cell disease (older than 21 years). But lessening the morbidity and mortality of the procedure, these studies could significantly change the management of selected inherited red blood cell diseases.
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