Progress Toward the Genetic Treatment of the β‐Thalassemias

A bstract : The β‐thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the β‐globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated β‐globin gene in autologous HSCs is a highly attractive alternative treatment. This strategy, which is simple in principle, raises major challenges in terms of controlling expression of the globin transgene, which ideally should be erythroid specific, differentiation‐ and stage‐restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, May et al. demonstrated in 2000 that an optimized combination of proximal and distal transcriptional control elements permits lineage‐specific and elevated β‐globin expression, resulting in therapeutic hemoglobin production and correction of anemia in β‐thalassemic mice. Several groups have by now replicated and extended these findings to various mouse models of severe hemoglobinopathies, thus fueling enthusiasm for a potential treatment of β‐thalassemia based on globin gene transfer. Current investigation focuses on safety issues and the need for improved vector production methodologies. The safe implementation of stem cell‐based gene therapy requires the prevention of the formation of replication‐competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non‐tissue‐specific vectors, by virtue of their late‐stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell‐based gene therapy.