Gene Therapy: Current Therapeutic Approaches for β-Thalassemia

Haema 2011; 2(3): 341-358

by Maria Georgomanoli1,2, Ekati Drakopoulou1,2, Eleni Papanikolaou1,2, Nicholas P. Anagnou1,2

1Laboratory of Cell and Gene Therapy, Basic Research Centre II, Biomedical Research Foundation of the Academy of Athens,
2Laboratory of Biology, University of Athens School of Medicine, Athens, Greece

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β-Thalassemias represent a heterogeneous group of monogeneic disorders affecting the β-globin chain synthesis. They are caused by more than 200 mutations, which result either in reduced or in absence of β-globin chain synthesis. As a consequence, there is an excess of α-globin molecules precipitating in red blood precursors, leading to impaired erythrocyte maturation, mechanical damage and ultimately to apoptosis. Current therapeutic approaches include blood transfusions, often combined with iron chelation and splenectomy, while the only so far definite treatment is that of HLA-matched hematopoietic stem cell transplantation. The multiple side-effects from regular blood transfusions, such as iron accumulation in vital organs, as well as the limited number of HLA-matched donors, have pointed towards the need for alternative treatments, such as gene therapy. The major breakthrough in β-thalassemia gene therapy occurred a decade ago with the development of globin lentiviral vectors, employed to deliver the therapeutic transgene, while the first proof that gene therapy can be curative came only recently from France, where a 18-year old thalassemic patient became transfusion independent, following bone marrow transplantation of lentivirally-transduced hematopoietic stem cells. Moreover, the emergence of new ‘key players’ in globin switching control and HbF expression, such as the transcription factors BCL11A and KLF1, and the development of the technology of induced pluripotent stem cells (iPS), constitute quite promising tools towards more effective gene therapy strategies.