A. A. ThompsonM. C. WaltersJ. KwiatkowskiJ. E.J. RaskoJ. A. RibeilS. HongengE. MagrinG. J. SchillerE. PayenM. SemeraroD. MoshousF. LefrereH. PuyP. BourgetA. MagnaniL. CaccavelliJ. S. DianaF. SuarezF. MonpouxV. BrousseC. PoirotC. BrouzesJ. F. MeritetC. PondarréY. BeuzardS. ChrétienT. LefebvreD. T. TeacheyU. AnurathapanP. J. HoC. Von KalleM. KletzelE. VichinskyS. SoniG. VeresO. NegreR. W. RossD. DavidsonA. PetrusichL. SandlerM. AsmalO. HermineM. De MontalembertS. Hacein-Bey-AbinaS. BlancheP. LeboulchM. CavazzanaBluebird Bio, Inc.Lucille Packard Children's HospitalUniversite Paris DescartesHôpital Necker Enfants MaladesThe University of SydneyHopital Cochin AP-HPRoyal Prince Alfred HospitalGerman Cancer Research CenterBrigham and Women's HospitalFaculty of Medicine, Ramathibodi Hospital, Mahidol UniversityHopital de BicetreNorthwestern University Feinberg School of MedicineCEA Fontenay aux RosesUCSF Benioff Children's Hospital OaklandUniversity of PennsylvaniaUniversite Paris 7- Denis DiderotDavid Geffen School of Medicine at UCLACentenary Institute of Cancer Medicine and Cell BiologyHopital Louis-MourierSorbonne UniversiteCentre Hospitalier Intercommunal CreteilImagine InstituteGroupe Hospitalier Universitaire Ouest2019-08-282019-08-282018-04-19New England Journal of Medicine. Vol.378, No.16 (2018), 1479-149315334406002847932-s2.0-85045833861https://repository.li.mahidol.ac.th/handle/123456789/46752Copyright © 2018 Massachusetts Medical Society. 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 patien with β-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusiondependent β-thalassemia. METHODS: In two phase 1-2 studies, we obtained mobilized autologos 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 replicatin-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/β 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 witout serious adverse events related to the drug product.Mahidol UniversityMedicineArticleSCOPUS10.1056/NEJMoa1705342