title: Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction.
abstract: Genetic defects in the purine salvage enzyme adenosine deaminase (ADA) lead to severe combined immunodeficiency (SCID) with profound depletion of T, B, and natural killer cell lineages. Human leukocyte antigen-matched allogeneic hematopoietic stem cell transplantation (HSCT) offers a successful treatment option. However, individuals who lack a matched donor must receive mismatched transplants, which are associated with considerable morbidity and mortality. Enzyme replacement therapy (ERT) for ADA-SCID is available, but the associated suboptimal correction of immunological defects leaves patients susceptible to infection. Here, six children were treated with autologous CD34-positive hematopoietic bone marrow stem and progenitor cells transduced with a conventional gammaretroviral vector encoding the human ADA gene. All patients stopped ERT and received mild chemotherapy before infusion of gene-modified cells. All patients survived, with a median follow-up of 43 months (range, 24 to 84 months). Four of the six patients recovered immune function as a result of engraftment of gene-corrected cells. In two patients, treatment failed because of disease-specific and technical reasons: Both restarted ERT and remain well. Of the four reconstituted patients, three remained off enzyme replacement. Moreover, three of these four patients discontinued immunoglobulin replacement, and all showed effective metabolic detoxification. All patients remained free of infection, and two cleared problematic persistent cytomegalovirus infection. There were no adverse leukemic side effects. Thus, gene therapy for ADA-SCID is safe, with effective immunological and metabolic correction, and may offer a viable alternative to conventional unrelated donor HSCT.
authors.affiliation: Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, University College London, London WC1N 1EH, UK. h.gaspar@ich.ucl.ac.uk
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.forename: Samantha
authors.initials: S
authors.lastname: Cooray
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Parsley
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Stuart
authors.initials: S
authors.lastname: Adams
authors.forename: Emma
authors.initials: E
authors.lastname: Bjorkegren
authors.forename: Jinhua
authors.initials: J
authors.lastname: Bayford
authors.forename: Lucinda
authors.initials: L
authors.lastname: Brown
authors.forename: E Graham
authors.initials: EG
authors.lastname: Davies
authors.forename: Paul
authors.initials: P
authors.lastname: Veys
authors.forename: Lynette
authors.initials: L
authors.lastname: Fairbanks
authors.forename: Victoria
authors.initials: V
authors.lastname: Bordon
authors.forename: Theoni
authors.initials: T
authors.lastname: Petropoulou
authors.forename: Theoni
authors.initials: T
authors.lastname: Petropolou
authors.forename: Christine
authors.initials: C
authors.lastname: Kinnon
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000361:Agammaglobulinemia / Q000276:immunology / Q000628:therapy*; D002675:Child, Preschool; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000243:Adenosine Deaminase