I. GENE THERAPY FOR SICKLE CELL DISEASE

The ability to efficiently insert a gene into repopulating hematopoietic cells and to achieve regulated expression in specific hematopoietic lineages would create many therapeutic opportunities.1 Indeed, sickle cell anemia has long been recognized as a potential candidate for the development of gene therapy approaches. Despite con-siderable effort over nearly 20 years, progress toward the goal of implementing gene therapy for sickle cell anemia has been slow. The relatively low efficiencies of gene transfer with conventional, murine oncoretroviral vectors coupled with the requirement for very high level globin gene expression in differentiating erythroblasts have been major barriers to rapid progress. Several con-vergent avenues of research to be reviewed in this sec-tion have culminated in the recent demonstration that the sickling phenotype can be corrected by retroviral vector mediated gene transfer into repopulating stem cells in murine models of sickle cell anemia.2 Develop-ment of these models required considerable effort in that both the mouse α- and β-globin genes had to be deleted and the human α and βS genes had to be introduced into the germline and coexpressed at relatively equal levels.3 Another major breakthrough that facilitated progress was the adoption of lentiviral vectors based on human im-munodeficiency virus (HIV) for globin gene transfer.4 This proof-of-principle demonstration that the sickling phenotype can be corrected by gene transfer has set the stage for critically evaluating the remaining problems to be solved before gene therapy for sickle cell anemia can be introduced into the clinic. Stem Cell Targeted Gene Transfe