title: Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.
abstract: BACKGROUND
  X-linked severe combined immunodeficiency due to a mutation in the gene encoding the common gamma (gamma(c)) chain is a lethal condition that can be cured by allogeneic stem-cell transplantation. We investigated whether infusion of autologous hematopoietic stem cells that had been transduced in vitro with the gamma(c) gene can restore the immune system in patients with severe combined immunodeficiency.
  
  
  METHODS
  CD34+ bone marrow cells from five boys with X-linked severe combined immunodeficiency were transduced ex vivo with the use of a defective retroviral vector. Integration and expression of the gamma(c) transgene and development of lymphocyte subgroups and their functions were sequentially analyzed over a period of up to 2.5 years after gene transfer.
  
  
  RESULTS
  No adverse effects resulted from the procedure. Transduced T cells and natural killer cells appeared in the blood of four of the five patients within four months. The numbers and phenotypes of T cells, the repertoire of T-cell receptors, and the in vitro proliferative responses of T cells to several antigens after immunization were nearly normal up to two years after treatment. Thymopoiesis was documented by the presence of naive T cells and T-cell antigen-receptor episomes and the development of a normal-sized thymus gland. The frequency of transduced B cells was low, but serum immunoglobulin levels and antibody production after immunization were sufficient to avoid the need for intravenous immunoglobulin. Correction of the immunodeficiency eradicated established infections and allowed patients to have a normal life.
  
  
  CONCLUSIONS
  Ex vivo gene therapy with gamma(c) can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency.
authors.affiliation: Laboratoire INSERM, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Frédérique
authors.initials: F
authors.lastname: Carlier
authors.forename: Cécile
authors.initials: C
authors.lastname: Bouneaud
authors.forename: Christophe
authors.initials: C
authors.lastname: Hue
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: De Villartay
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wulffraat
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sorensen
authors.forename: Sophie
authors.initials: S
authors.lastname: Dupuis-Girod
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: E Graham
authors.initials: EG
authors.lastname: Davies
authors.forename: Wietse
authors.initials: W
authors.lastname: Kuis
authors.forename: Lilly
authors.initials: L
authors.lastname: Leiva
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
mesh_terms: D000906:Antibodies / Q000097:blood; D015703:Antigens, CD / Q000032:analysis; D001854:Bone Marrow Cells; D008040:Genetic Linkage; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D016756:Immunoglobulins, Intravenous; D007223:Infant; D007694:Killer Cells, Natural / Q000502:physiology; D018655:Lymphocyte Count; D008297:Male; D008979:Moloney murine leukemia virus / Q000235:genetics; D018121:Receptors, Cytokine / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D014161:Transduction, Genetic; D019076:Transgenes; D014960:X Chromosome
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D007136:Immunoglobulins; D016756:Immunoglobulins, Intravenous; D018121:Receptors, Cytokine