Development and Recent Progresses of Gene Therapy for β-Thalassemia

Abstract

β-thalassemias are among the most common inherited monogenic disorders worldwide due to mutations in the β-globin gene that reduce or abolish the production of the β-globin chain resulting in transfusion-dependent chronic anemia. Currently, the only curative treatment is allogeneic hematopoietic stem cells (HSCs) transplantation, but this option is limited by the a vailability of HLA-matched donor. Gene therapy, based on autologous transplantation of genetically corrected HSCs, holds the promise to treat patients lacking a compati ble bone marrow donor. I nit ial attempts of gene transfer have been unsuccessful due to limitations of available vectors to stably transfer a globin gene in HSCs and reach high and regulated expression in the erythroid progeny. With the advent of lentiviral vectors (LVs), based on human immunodeficiency virus, many of the initial limitations have been overcome. Since 2000 when Sadelain and co-workers first demonstrated successful globin gene transfer in murine thalassemia models with improvement of the phenotype using a recombinant β globin/LV, several other groups have developed different vectors encoding either β, γ or mutated globin genes and confirmed these results in both murine models and erythroid progeny derived from patient’s HSCs. In light of these encouraging results, research has recently moved into clinical trials that are ongoing or soon to begin. One participant in an ongoing gene transfer trial for β-thalassemia has achieved clinical benefit with elimination of his transfusi on re quirement. Here , dev elopmen t and recent progress of gene therapy for β-thalassemia is reviewed.