title: Gene therapy for immunodeficiency due to adenosine deaminase deficiency.
abstract: BACKGROUND
  We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency.
  
  
  METHODS
  We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells.
  
  
  RESULTS
  All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one).
  
  
  CONCLUSIONS
  Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Federica
authors.initials: F
authors.lastname: Cattaneo
authors.forename: Stefania
authors.initials: S
authors.lastname: Galimberti
authors.forename: Ulrike
authors.initials: U
authors.lastname: Benninghoff
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Luciano
authors.initials: L
authors.lastname: Callegaro
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.forename: Grazia
authors.initials: G
authors.lastname: Andolfi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mirolo
authors.forename: Immacolata
authors.initials: I
authors.lastname: Brigida
authors.forename: Antonella
authors.initials: A
authors.lastname: Tabucchi
authors.forename: Filippo
authors.initials: F
authors.lastname: Carlucci
authors.forename: Martha
authors.initials: M
authors.lastname: Eibl
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
authors.forename: Hamoud
authors.initials: H
authors.lastname: Al-Mousa
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Al Ghonaium
authors.forename: Alina
authors.initials: A
authors.lastname: Ferster
authors.forename: Andrea
authors.initials: A
authors.lastname: Duppenthaler
authors.forename: Luigi
authors.initials: L
authors.lastname: Notarangelo
authors.forename: Uwe
authors.initials: U
authors.lastname: Wintergerst
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Buckley
authors.forename: Marco
authors.initials: M
authors.lastname: Bregni
authors.forename: Sarah
authors.initials: S
authors.lastname: Marktel
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Valsecchi
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Roberto
authors.initials: R
authors.lastname: Miniero
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics*; D018952:Antigens, CD34 / Q000235:genetics*; D001854:Bone Marrow Cells / Q000276:immunology; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005500:Follow-Up Studies; D015316:Genetic Therapy; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D018655:Lymphocyte Count; D012190:Retroviridae; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000628:therapy*; D014161:Transduction, Genetic; D019172:Transplantation Conditioning
chemical_list: D018952:Antigens, CD34; D000243:Adenosine Deaminase