Cell and Gene Therapy for Beta-Thalassemias: Advances and Prospects

Cell and Gene Therapy for the Beta-Thalassemia: Advances and Prospects

The beta-thalassemias are inherited anemias caused by mutations that severely reduce or abolish expression of the beta-globin gene. Like sickle cell disease, a related beta-globin gene disorder, they are ideal candidates for performing a genetic correction in patient hematopoietic stem cells (HSCs). The most advanced approach utilizes complex lentiviral vectors encoding the human-globin gene, as first reported by May et al. in 2000. Considerable progress toward the clinical implementation of this approach has been made in the past five years, based on effective CD34+ cell mobilization and improved lentiviral vector manufacturing. Four trials have been initiated in the United States and Europe. Of 16 evaluable subjects, 6 have achieved transfusion independence. One of them developed a durable clonal expansion, which regressed after several years without transformation. Although globin lentiviral vectors have so far proven to be safe, this occurrence suggests that powerful insulators with robust enhancer-blocking activity will further enhance this approach. The combined discovery of Bcl11a-mediated y-globin gene silencing and advances in gene editing are the foundations for another gene therapy approach, which aims to reactivate fetal hemoglobin (HbF) production. Its clinical translation will hinge on the safety and efficiency of gene targeting in true HSCs and the induction of sufficient levels of HbF to achieve transfusion independence. Altogether, the progress achieved over the past 15 years bodes well for finding a genetic cure for severe globin disorders in the next decade.

THE BETA-THALASSEMIAS ARE inherited blood disorders that result from the defective or absent production of the beta chain of hemoglobin. Over 120 different mutations, most of them affecting the beta-globin gene itself, have been identified around the world.
1 The severe form of the disease, known
as beta-thalassemia major, is treated with life-long transfusions of donor red blood cells (RBCs), which the thalassemic bone marrow is itself unable to produce. Transfusion therapy does not correct ineffective erythropoiesis and exacerbates systemic iron accumulation. Iron chelation is required to curb the iron overload that inexorably builds up in chronically transfused patients.

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