Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 363, Issue 4, Pages 355-364Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1000164
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Funding
- INSERM
- Association Francaise contre les Myopathies [AT0203]
- European Commission [QLK3-CT-1999-00859]
- Concerted Safety and Efficiency Evaluation of Retroviral Transgenesis in Gene Therapy of Inherited Diseases [005242]
- Gene Therapy of Hematopoietic Stem Cells for Inherited Diseases [QLK3-CT-2001-00427]
- Agence Nationale de la Recherche [05-MRAR-004]
- Programme Hospitalier de Recherche Clinique of the Health Ministry [PHRC AOM 08064-P071204]
- Assistance Publique-Hopitaux de Paris
- Fondation de l'Avenir
- Institut Pasteur and College de France
- National Institutes of Health [AI52845, AI082020]
- Akademie der Naturforscher Leopoldina [BMBF-LPD 9901/8-149]
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BACKGROUND The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common gamma chain. METHODS The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of gamma chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up. RESULTS Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell-receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients' health. CONCLUSIONS After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia.
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