Recent advances in globin gene transfer for the treatment of beta-thalassemia and sickle cell anemia

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Abstract
The beta-thalassemias and sickle cell anemia are severe congenital anemias for which there is presently no curative therapy other than allogeneic hematopoietic stem cell transplantation. This therapeutic option, however, is not available to most patients due to the lack of an HLA-matched bone marrow donor. The transfer of a regulated globin gene in autologous hematopoietic stem cells is therefore a highly attractive alternative treatment. This strategy, simple in principle, raises major challenges in terms of controlling transgene expression, which ideally should be erythroid specific, differentiation and stage restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, May et al. demonstrated that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and elevated beta-globin expression in vivo, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Several groups have extended these findings to various models of beta-thalassemia and sickle cell disease. While the addition of the wild-type beta-globin gene is naturally suited for treating beta-thalassemia, several alternatives have been proposed for the treatment of sickle cell disease, using either gamma or mutant beta-globin gene addition, trans-splicing or RNA interference. These recent advances bode well for the clinical investigation of stem cell-based gene therapy in the severe hemoglobinopathies.