The New England Journal of Medicine: Gene Therapy in a Patient with Sickle Cell Disease

The New England Journal of Medicine: Gene Therapy in a Patient with Sickle Cell Disease

<br /><a href="http://www.nejm.org/doi/10.1056/NEJMoa1609677">this is a shotcut to the article</a>

Gene Therapy in a Patient with Sickle Cell Disease
Jean-Antoine Ribeil, M.D., Ph.D., Salima Hacein-Bey-Abina, Pharm.D., Ph.D., Emmanuel Payen, Ph.D., Alessandra Magnani, M.D., Ph.D., Michaela Semeraro, M.D., Ph.D., Elisa Magrin, Ph.D., Laure Caccavelli, Ph.D., Benedicte Neven, M.D., Ph.D., Philippe Bourget, Pharm.D., Ph.D., Wassim El Nemer, Ph.D., Pablo Bartolucci, M.D., Ph.D., Leslie Weber, M.Sc., Hervé Puy, M.D., Ph.D., Jean-François Meritet, Ph.D., David Grevent, M.D., Yves Beuzard, M.D., Stany Chrétien, Ph.D., Thibaud Lefebvre, M.D., Robert W. Ross, M.D., Olivier Negre, Ph.D., Gabor Veres, Ph.D., Laura Sandler, M.P.H., Sandeep Soni, M.D., Mariane de Montalembert, M.D., Ph.D., Stéphane Blanche, M.D., Philippe Leboulch, M.D., and Marina Cavazzana, M.D., Ph.D.
N Engl J Med 2017; 376:848-855March 2, 2017DOI: 10.1056/NEJMoa1609677

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Sickle cell disease results from a homozygous missense mutation in the β-globin gene that causes polymerization of hemoglobin S. Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector–mediated addition of an antisickling β-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling β-globin remained high (approximately 50% of β-like–globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease. (Funded by Bluebird Bio and others; HGB-205 ClinicalTrials.gov number, NCT02151526.)
Supported by Bluebird Bio and by a grant to the Biotherapy Clinical Investigation Center from Assistance Publique–Hôpitaux de Paris and INSERM.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. Ribeil and Hacein-Bey-Abina and Drs. Leboulch and Cavazzana contributed equally to this article
We thank the staff at Necker Children’s Hospital for their important contributions to the care of the patient described in this article; our colleagues Zoubida Karim, Ph.D., of Université Paris Diderot, Laurent Kiger, Ph.D., and Marie Georgine Rakotoson, Ph.D., of Institut Mondor de Recherche Biomédicale, and Michel Bahuau of Centre Hospitalier Universitaire Henri Mondor for their contributions to the study; Laurent Kiger for creating and analyzing the oxygen-binding curves; Marie Georgine Rakotoson for creating and analyzing the density curves; Michel Bahuau for assessing the patient’s enzyme levels; Frédéric Galacteros for providing data on normal enzyme levels in patients with sickle cell disease; Mohammed Asmal, M.D., Ph.D., David Davidson, M.D., Tara O’Meara, Lilian Yengi, Ph.D., and Philip Gregory, Ph.D., of Bluebird Bio for their contributions to the study design and execution and for their critical review of an earlier version of the manuscript; and Katherine Lewis, an employee of Bluebird Bio, for editorial support in preparation of an earlier version of the manuscript.
SOURCE INFORMATION
From the Departments of Biotherapy (J.-A.R., A.M., E.M., L.C., M.C.), Clinical Pharmacy (P. Bourget), Pediatric Neuroradiology (D.G.), General Pediatrics (M.M.), and Pediatric Immunology–Hematology Unit (B.N., S.B.), Necker Children’s Hospital, Assistance Publique–Hôpitaux de Paris (AP-HP), Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM (J.-A.R., A.M., E.M., L.C., L.W., M.C.), Unité de Technologies Chimiques et Biologiques pour la Santé, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8258, INSERM Unité 1022, Faculté de Pharmacie de Paris, Université Paris Descartes, Chimie ParisTech (S.H.-B.-A.), Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hôpital Kremlin-Bicêtre, AP-HP, Le Kremlin-Bicêtre (S.H.-B.-A.), the Institute of Emerging Diseases and Innovative Therapies, Imagine Institute, Université Paris Descartes, Sorbonne Paris Cité University (M.S., B.N., L.W., M.C.), Mère-Enfant Clinical Investigation Center, Groupe Hospitalier Necker Cochin (M.S.), Université Paris Diderot, Sorbonne Paris Cité University, INSERM Institut National de Transfusion Sanguine, Unité Biologie Intégrée du Globule Rouge, Laboratoire d’Excellence GR-Ex (W.E.N.), and Laboratoires de Virologie, Hôpital Cochin (J.-F.M.), Paris, Atomic and Alternative Energy Commission, Université Paris-Sud, Fontenay-aux-Roses (E.P., Y.B., S.C., P.L.), Institut Mondor de Recherche Biomédicale, Equipe 2, Centre de Référence des Syndromes Drépanocytaires Majeurs, Centre Hospitalier Universitaire Henri Mondor, AP-HP, Laboratoire d’Excellence GR-Ex, Créteil (P. Bartolucci), and Université Paris Diderot, Sorbonne Paris Cité University, INSERM Unité 1149, Hôpital Louis-Mourier, AP-HP, Laboratoire d’Excellence GR-Ex, Colombes (H.P., T.L.) — all in France; Bluebird Bio, Cambridge (R.W.R., O.N., G.V., L.S., S.S.), and Brigham and Women’s Hospital and Harvard Medical School, Boston (P.L.) — both in Massachusetts; and Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (P.L.).
Address reprint requests to Dr. Cavazzana at the Biotherapy Department, Necker Children’s Hospital, Assistance Publique–Hôpitaux de Paris, 149 rue de Sèvres, 75015 Paris, France, or at m.cavazzana@aphp.fr; or to Dr. Leboulch at the Institute of Emerging Diseases and Innovative Therapies, 18, rte du Panorama BP-6, 92265 Fontenay-aux-Roses, France, or at pleboulch@rics.bwh.harvard.edu.
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MEDIA IN THIS ARTICLE
FIGURE 1
Engraftment with Transduced Cells and Therapeutic Gene Expression in the Patient.
FIGURE 2
Results of Sickle Cell Disease–Specific Red-Cell Assays.
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