Details

Autor(en) / Beteiligte

• 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

Titel

Gene Therapy in Patients with Transfusion-Dependent [beta]-Thalassemia

Ist Teil von

• The New England journal of medicine, 2018-04, Vol.378 (16), p.1479

Ort / Verlag

Boston: Massachusetts Medical Society

Erscheinungsjahr

2018

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526.)