title: Successful reconstitution of immunity in ADA-SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning.
abstract: Gene therapy is a promising treatment option for monogenic diseases, but success has been seen in only a handful of studies thus far. We now document successful reconstitution of immune function in a child with the adenosine deaminase (ADA)-deficient form of severe combined immunodeficiency (SCID) following hematopoietic stem cell (HSC) gene therapy. An ADA-SCID child who showed a poor response to PEG-ADA enzyme replacement was enrolled into the clinical study. Following cessation of enzyme replacement therapy, autologous CD34(+) HSCs were transduced with an ADA-expressing gammaretroviral vector. Gene-modified cells were reinfused following one dose of preconditioning chemotherapy. Two years after the procedure, immunological and biochemical correction has been maintained with progressive increase in lymphocyte numbers, reinitiation of thymopoiesis, and systemic detoxification of ADA metabolites. Sustained vector marking with detection of polyclonal vector integration sites in multiple cell lineages and detection of ADA activity in red blood cells suggests transduction of early hematopoietic progenitors. No serious side effects were seen either as a result of the conditioning procedure or due to retroviral insertion. Gene therapy is an effective treatment option for the treatment of ADA-SCID.
authors.affiliation: Molecular Immunology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. h.gaspar@ich.ucl.ac.uk
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.forename: Emma
authors.initials: E
authors.lastname: Bjorkegren
authors.forename: Kate
authors.initials: K
authors.lastname: Parsley
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.forename: Doug
authors.initials: D
authors.lastname: King
authors.forename: Joanna
authors.initials: J
authors.lastname: Sinclair
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Aris
authors.initials: A
authors.lastname: Giannakopoulos
authors.forename: Stuart
authors.initials: S
authors.lastname: Adams
authors.forename: Lynette D
authors.initials: LD
authors.lastname: Fairbanks
authors.forename: Jane
authors.initials: J
authors.lastname: Gaspar
authors.forename: Lesley
authors.initials: L
authors.lastname: Henderson
authors.forename: Jin Hua
authors.initials: JH
authors.lastname: Xu-Bayford
authors.forename: E Graham
authors.initials: EG
authors.lastname: Davies
authors.forename: Paul A
authors.initials: PA
authors.lastname: Veys
authors.forename: Christine
authors.initials: C
authors.lastname: Kinnon
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019070:Cell Lineage; D002478:Cells, Cultured; D002675:Child, Preschool; D005500:Follow-Up Studies; D018628:Gene Dosage; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D006801:Humans; D007223:Infant; D008297:Male; D011092:Polyethylene Glycols; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019172:Transplantation Conditioning
chemical_list: D011092:Polyethylene Glycols; D000243:Adenosine Deaminase