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Title: Gene therapy in patients with transfusion-dependent β-thalassemia
Authors: A. A. Thompson
M. C. Walters
J. Kwiatkowski
J. E.J. Rasko
J. A. Ribeil
S. Hongeng
E. Magrin
G. J. Schiller
E. Payen
M. Semeraro
D. Moshous
F. Lefrere
H. Puy
P. Bourget
A. Magnani
L. Caccavelli
J. S. Diana
F. Suarez
F. Monpoux
V. Brousse
C. Poirot
C. Brouzes
J. F. Meritet
C. Pondarré
Y. Beuzard
S. Chrétien
T. Lefebvre
D. T. Teachey
U. Anurathapan
P. J. Ho
C. Von Kalle
M. Kletzel
E. Vichinsky
S. Soni
G. Veres
O. Negre
R. W. Ross
D. Davidson
A. Petrusich
L. Sandler
M. Asmal
O. Hermine
M. De Montalembert
S. Hacein-Bey-Abina
S. Blanche
P. Leboulch
M. Cavazzana
Bluebird Bio, Inc.
Lucille Packard Children's Hospital
Universite Paris Descartes
Hôpital Necker Enfants Malades
The University of Sydney
Hopital Cochin AP-HP
Royal Prince Alfred Hospital
German Cancer Research Center
Brigham and Women's Hospital
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Hopital de Bicetre
Northwestern University Feinberg School of Medicine
CEA Fontenay aux Roses
UCSF Benioff Children's Hospital Oakland
University of Pennsylvania
Universite Paris 7- Denis Diderot
David Geffen School of Medicine at UCLA
Centenary Institute of Cancer Medicine and Cell Biology
Hopital Louis-Mourier
Sorbonne Universite
Centre Hospitalier Intercommunal Creteil
Imagine Institute
Groupe Hospitalier Universitaire Ouest
Keywords: Medicine
Issue Date: 19-Apr-2018
Citation: New England Journal of Medicine. Vol.378, No.16 (2018), 1479-1493
Abstract: Copyright © 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.
ISSN: 15334406
Appears in Collections:Scopus 2018

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