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Open Access Publications from the University of California

Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia.

  • Author(s): Thompson, Alexis A
  • Walters, Mark C
  • Kwiatkowski, Janet
  • Rasko, John EJ
  • Ribeil, Jean-Antoine
  • Hongeng, Suradej
  • Magrin, Elisa
  • Schiller, Gary J
  • Payen, Emmanuel
  • Semeraro, Michaela
  • Moshous, Despina
  • Lefrere, Francois
  • Puy, Hervé
  • Bourget, Philippe
  • Magnani, Alessandra
  • Caccavelli, Laure
  • Diana, Jean-Sébastien
  • Suarez, Felipe
  • Monpoux, Fabrice
  • Brousse, Valentine
  • Poirot, Catherine
  • Brouzes, Chantal
  • Meritet, Jean-François
  • Pondarré, Corinne
  • Beuzard, Yves
  • Chrétien, Stany
  • Lefebvre, Thibaud
  • Teachey, David T
  • Anurathapan, Usanarat
  • Ho, P Joy
  • von Kalle, Christof
  • Kletzel, Morris
  • Vichinsky, Elliott
  • Soni, Sandeep
  • Veres, Gabor
  • Negre, Olivier
  • Ross, Robert W
  • Davidson, David
  • Petrusich, Alexandria
  • Sandler, Laura
  • Asmal, Mohammed
  • Hermine, Olivier
  • De Montalembert, Mariane
  • Hacein-Bey-Abina, Salima
  • Blanche, Stéphane
  • Leboulch, Philippe
  • Cavazzana, Marina
  • et al.

BACKGROUND:Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent β-thalassemia. After previously establishing that lentiviral transfer of a marked β-globin (βA-T87Q) gene could substitute for long-term red-cell transfusions in a patient with β-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent β-thalassemia. METHODS:In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent β-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbAT87Q, transfusion requirements, and average vector copy number. RESULTS:At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-β0/β0 genotype had stopped receiving red-cell transfusions; the levels of HbAT87Q ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a β0/β0 genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. CONCLUSIONS:Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe β-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 numbers, NCT01745120 and NCT02151526 .).

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