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N Engl J Med. 2014 Oct 9;371(15):1407-17. doi: 10.1056/NEJMoa1404588.

A modified γ-retrovirus vector for X-linked severe combined immunodeficiency.

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From the Departments of Biotherapy (S.H.-B.-A., J. Blondeau, L.C., F.T., M.C.) and Immunology and Pediatric Hematology (S.B., G.C., D.M., B.N., C.P., F.T., A.F.) and the Centre d'Étude des Déficits Immunitaires (C.P.), Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), the Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM (S.H.-B.-A., J. Blondeau, L.C., F.T., M.C.), Unité de Technologies Chimiques et Biologiques pour la Santé, Centre National de la Recherche Scientifique, 8258-INSERM Unité 1022, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes (S.H.-B.-A.), Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, AP-HP, Le Kremlin-Bicêtre (S.H.-B.-A.), Imagine Institute, Paris Descartes-Sorbonne Paris Cité University (S.B., J. Blondeau, L.C., D.M., B.N., C.P., E.S., A.F., M.C.), INSERM Unités Mixtes de Recherche 1163, Laboratory of Human Lymphohematopoiesis (J. Blondeau, L.C., E.S., F.T., A.F., M.C.), Groupe Immunoscope, Immunology Department, Institut Pasteur (A.L.), and Collège de France (A.F.) - all in Paris; Division of Hematology-Oncology (S.-Y.P., H.B., D.G., C.E.H., G.H., L.E.L., W.B.L., D.A.W.) and Division of Immunology (L.D.N.), Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute (S.-Y.P., D.G., L.E.L., W.B.L., D.A.W.), Harvard Medical School (S.-Y.P., M.A., L.E.L., W.B.L., J.R., L.E.S., A.T., L.D.N., D.A.W.), Center for Human Cell Therapy, Program in Cellular and Molecular Medicine, Boston Children's Hospital (M.A., J.R., L.E.S., A.T.), Division of Hematologic Malignancies, Dana-Farber Cancer Institute (J.R.), and the Manton Center for Orphan Disease Research (L.D.N.) - all in Boston; Great Ormond Street Hospital for Children NHS Foundation Trust (H.B.G., J.X.-B., A.J.T.) and Section of Molecular and Cellular Immunology, University College London Institute of Child Health (H.B.G., K.F.B., A.



In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1.


We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc).


All patients received bone marrow-derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients.


This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; numbers, NCT01410019, NCT01175239, and NCT01129544.).

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