Efficacy of gene therapy for X-linked severe combined immunodeficiency

Salima Hacein-Bey-Abina, Julia Hauer, Annick Lim, Capucine Picard, Gary P. Wang, Charles C. Berry, Chantal Martinache, Frédéric Rieux-Laucat, Sylvain Latour, Bernd H. Belohradsky, Lily Leiva, Ricardo Sorensen, Marianne Debré, Jean Laurent Casanova, Stephane Blanche, Anne Durandy, Frederic D. Bushman, Alain Fischer, Marina Cavazzana-Calvo

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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 γ chain. METHODS: The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of γ 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. (Funded by INSERM and others.)

Original languageEnglish
Pages (from-to)355-364
Number of pages10
JournalNew England Journal of Medicine
Issue number4
StatePublished - 22 Jul 2010
Externally publishedYes


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