Rounding up sickle cells with gene therapy

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Science Translational Medicine  15 Mar 2017:
Vol. 9, Issue 381, eaam9864
DOI: 10.1126/scitranslmed.aam9864


A report of a patient treated with ex vivo lentiviral gene transfer to hematopoietic stem cells shows the promise of gene therapy for sickle cell anemia.

Sickle cell disease affects millions of patients worldwide and is currently curable only through hematopoietic stem cell transplantation. The disease is caused by mutations in the HBB gene, which encodes beta-globin, one of the components of hemoglobin, the molecule in red blood cells that delivers oxygen to tissues throughout the body. The form of hemoglobin causing sickle cell anemia, called hemoglobin S (HbS), polymerizes after deoxygenization. The presence of HbS polymers gives red blood cells the characteristic sickle cell shape for which the disease is named and reduces the deformability of red blood cells, causing their premature lysis and depriving tissues of oxygen. Patients experience painful episodes of vaso-occlusive crises, a reduction in quality of life, and a shortened life expectancy.

A gene therapy study by Ribeil et al., conducted in France, has reported highly promising results after transfusion of autologous hematopoietic stem cells treated with a lentiviral vector encoding a therapeutic HBB gene. The authors report that a self-inactivating lentiviral vector carrying an HBB variant, βA-T87Q, with a mutation that reduces polymerization, was used ex vivo to treat stem cells collected from the patient. After gene transfer, the stem cells were engrafted into the patient, producing therapeutic HbAT87Q in amounts that were equal to the expression of endogenous HbS. No adverse events related to the gene therapy were reported over the 15-month duration of the study. Remarkably, after the treatment, the patient discontinued transfusions of red blood cells, experienced a cessation of sickle cell–related symptoms, and had rates of red blood cell sickling similar to his heterozygous mother, who is asymptomatic.

This highly encouraging case report, which follows a similarly promising study treating β-thalassemia, conducted by the same group, suggests the promise of gene therapy for sickle cell anemia. Longer-term follow-up studies to evaluate the permanence of the treatment are needed, and data from additional patients currently enrolled in an ongoing phase 1/2 clinical trial for the treatment will be eagerly awaited. However, this report adds to the growing number of success stories in the field of gene therapy and the number of previously untreatable conditions that are proving to be promising targets for gene therapy approaches.

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