ENGRAFTMENT OF IMMUNE-DEFICIENT MICE WITH PRIMITIVE HEMATOPOIETIC-CELLS FROM BETA-THALASSEMIA AND SICKLE-CELL-ANEMIA PATIENTS - IMPLICATIONS FOR EVALUATING HUMAN GENE-THERAPY PROTOCOLS

Permanent correction of genetic deficiencies of the hematopoietic syst em requires gene transfer into stem cells and long-term lineage specif ic expression after autologous transplantation. However, progress to d evelop gene therapy protocols has been hampered by the absence of in v ivo assays that detect genetically deficient human hematopoietic stem cells and their diseased differentiated progeny, The establishment of systems to transplant human cells into immune-deficient SCID mice prov ides such an assay, We report that primitive bone marrow cells from be ta-thalassemia major and sickle cell anemia patients engraft immune-de ficient mice, giving rise to high levels of human erythroid and myeloi d cells in response to treatment with human cytokines, The bone marrow of transplanted mice contained the entire erythroid lineage from BFU- E to mature erythrocytes expressing human gamma, beta or beta(s)-globi n, Moreover, human erythroid cells from mice transplanted with sickle cell anemia bone marrow showed characteristic sickling under reducing conditions in an in vifro assay, This model provides a powerful in viv e system that can be used to evaluate the efficiency of globin gene tr ansfer into primitive human hematopoietic cells, lineage-specfic expre ssion in mature erythrocytes, and ultimately correction of the cellula r defect found in the erythroid lineage.