title: Efficacy of gene therapy for X-linked severe combined immunodeficiency.
abstract: 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. (Funded by INSERM and others.)
authors.affiliation: Department of Biotherapy, Necker-Enfants Malades Hospital, Paris, France. salima.hacein-bey@nck.ap-hop-paris.fr
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: Julia
authors.initials: J
authors.lastname: Hauer
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Gary P
authors.initials: GP
authors.lastname: Wang
authors.forename: Charles C
authors.initials: CC
authors.lastname: Berry
authors.forename: Chantal
authors.initials: C
authors.lastname: Martinache
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.forename: Lily
authors.initials: L
authors.lastname: Leiva
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sorensen
authors.forename: Marianne
authors.initials: M
authors.lastname: Debré
authors.forename: Jean Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Stephane
authors.initials: S
authors.lastname: Blanche
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
mesh_terms: D018952:Antigens, CD34; D001402:B-Lymphocytes / Q000276:immunology; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000009:adverse effects; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics*; D007694:Killer Cells, Natural / Q000502:physiology; D018655:Lymphocyte Count; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018952:Antigens, CD34; C507941:IL2RG protein, human; D007136:Immunoglobulins; D053631:Interleukin Receptor Common gamma Subunit