Patients with sickle cell disease (scd) show extensive heterogeneity in both the severity of their clinical course and in the indices of cellular defects. Erythrocytes in patients with SCD show heterogeneity in size, shape, density and volume, are poorly deformable and have abnormal red cell membrane. It remains unknown to what extent these changes are due to intrinsic defects of erythrocytes from the presence of HbS or are extrinsic, due to secondary consequence from interactions of the HbS- containing RBC with abnormal microvasculature, activated leukocytes and endothelial cells and thrombotic events. Gene therapy to correct the genetic defect of RBC by insertion of normal beta- or gamma-globin genes into hematopoietic progenitors (HPC) may be able to prevent primary or secondary defects from developing. It is our central hypothesis that novel models for production of human erythrocytes from CD34+ Hematopoietic progenitor cells will allow us to determine the relative role of intrinsic verses extrinsic factors on RBC abnormalities and to study the potential to reverse these abnormalities by gene therapy. To test this hypothesis, we will perform the following two specific aims: 1) develop an in vitro model for production of human erythrocytes form human Cd34+ progenitor cells, using cytokine-driven progenitor expansion and erythroid differentiation and 2) develop an in vivo model for production of human erythrocytes for CD34+ progenitor cells in mice which both accept human xenografts (beige,nude/xid) and are deficient in endogenous erythropoiesis (beta-thal transgenic). These parallel in vitro and in vivo models will produce novel systems for studying human erythropoiesis. In collaboration with Drs. Meiselman and Fisher, we will pose unique questions about the intrinsic versus extrinsic nature of the myriad defects that have been characterized in erythrocytes from SCD patients. Additionally, we will be able to determine the efficacy of gene transfer to correct abnormalities of erythrocytes developed from CD34+ from patients with SCD.
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