• Karine Sii-Felice, Marie Giorgi, Philippe Leboulch, and Emmanuel Payen.
• UMR E007, Service of Innovative Therapies, Institute of Biology François Jacob and University Paris Saclay, CEA Paris Saclay, Fontenay-aux-Roses, France.
• Exp. Hematol. 2018 Aug 1; 64: 12-32.

AbstractThe β-hemoglobinopathies, transfusion-dependent β-thalassemia and sickle cell disease, are the most prevalent inherited disorders worldwide and affect millions of people. Many of these patients have a shortened life expectancy and suffer from severe morbidity despite supportive therapies, which impose an enormous financial burden to societies. The only available curative therapy is allogeneic hematopoietic stem cell transplantation, although most patients do not have an HLA-matched sibling donor, and those who do still risk life-threatening complications. Therefore, gene therapy by one-time ex vivo modification of hematopoietic stem cells followed by autologous engraftment is an attractive new therapeutic modality. The first proof-of-principle of conversion to transfusion independence by means of a lentiviral vector expressing a marked and anti-sickling βT87Q-globin gene variant was reported a decade ago in a patient with transfusion-dependent β-thalassemia. In follow-up multicenter Phase II trials with an essentially identical vector (termed LentiGlobin BB305) and protocol, 12 of the 13 patients with a non-β0/β0 genotype, representing more than half of all transfusion-dependent β-thalassemia cases worldwide, stopped red blood cell transfusions with total hemoglobin levels in blood approaching normal values. Correction of biological markers of dyserythropoiesis was achieved in evaluated patients. In nine patients with β0/β0 transfusion-dependent β-thalassemia or equivalent severity (βIVS1-110), median annualized transfusion volume decreased by 73% and red blood cell transfusions were stopped in three patients. Proof-of-principle of therapeutic efficacy in the first patient with sickle cell disease was also reported with LentiGlobin BB305. Encouraging results were presented in children with transfusion-dependent β-thalassemia in another trial with the GLOBE lentiviral vector and several other gene therapy trials are currently open for both transfusion-dependent β-thalassemia and sickle cell disease. Phase III trials are now under way and should help to determine benefit/risk/cost ratios to move gene therapy toward clinical practice.Copyright © 2018 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

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