title: Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency.
abstract: Adenosine deaminase (ADA) deficiency is a rare, autosomal-recessive systemic metabolic disease characterized by severe combined immunodeficiency (SCID). The treatment of choice for ADA-deficient SCID (ADA-SCID) is hematopoietic stem cell transplant from an HLA-matched sibling donor, although <25% of patients have such a donor available. Enzyme replacement therapy (ERT) partially and temporarily relieves immunodeficiency. We investigated the medium-term outcome of gene therapy (GT) in 18 patients with ADA-SCID for whom an HLA-identical family donor was not available; most were not responding well to ERT. Patients were treated with an autologous CD34(+)-enriched cell fraction that contained CD34(+) cells transduced with a retroviral vector encoding the human ADA complementary DNA sequence (GSK2696273) as part of single-arm, open-label studies or compassionate use programs. Overall survival was 100% over 2.3 to 13.4 years (median, 6.9 years). Gene-modified cells were stably present in multiple lineages throughout follow up. GT resulted in a sustained reduction in the severe infection rate from 1.17 events per person-year to 0.17 events per person-year (n = 17, patient 1 data not available). Immune reconstitution was demonstrated by normalization of T-cell subsets (CD3(+), CD4(+), and CD8(+)), evidence of thymopoiesis, and sustained T-cell proliferative capacity. B-cell function was evidenced by immunoglobulin production, decreased intravenous immunoglobulin use, and antibody response after vaccination. All 18 patients reported infections as adverse events; infections of respiratory and gastrointestinal tracts were reported most frequently. No events indicative of leukemic transformation were reported. Trial details were registered at www.clinicaltrials.gov as #NCT00598481.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Cicalese
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrua
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Laura
authors.initials: L
authors.lastname: Castagnaro
authors.affiliation: Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Pajno
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Federica
authors.initials: F
authors.lastname: Barzaghi
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Stefania
authors.initials: S
authors.lastname: Giannelli
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Dionisio
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Immacolata
authors.initials: I
authors.lastname: Brigida
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Bonopane
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Miriam
authors.initials: M
authors.lastname: Casiraghi
authors.affiliation: Department of Medical Biotechnology, University of Siena, Siena, Italy;
authors.forename: Antonella
authors.initials: A
authors.lastname: Tabucchi
authors.affiliation: Department of Medical Biotechnology, University of Siena, Siena, Italy;
authors.forename: Filippo
authors.initials: F
authors.lastname: Carlucci
authors.affiliation: Division of Immunology and Allergy, The Hospital for Sick Children, Toronto, Canada;
authors.forename: Eyal
authors.initials: E
authors.lastname: Grunebaum
authors.affiliation: Division of Immunology and Allergy, Hamad Medical Corporation, Doha, Qatar;
authors.forename: Mehdi
authors.initials: M
authors.lastname: Adeli
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Robbert G
authors.initials: RG
authors.lastname: Bredius
authors.affiliation: Department of Pediatrics, University of California-San Francisco, San Francisco, CA;
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.affiliation: Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, Israel;
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: Department of Pediatrics, Section of Pediatric Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey;
authors.forename: Ilhan
authors.initials: I
authors.lastname: Tezcan
authors.affiliation: GSK Research and Development, GlaxoSmithKline, Stevenage, United Kingdom, and Upper Merion, PA;
authors.forename: Katie
authors.initials: K
authors.lastname: Rolfe
authors.affiliation: GSK Research and Development, GlaxoSmithKline, Stevenage, United Kingdom, and Upper Merion, PA;
authors.forename: Erika
authors.initials: E
authors.lastname: De Boever
authors.affiliation: GSK Research and Development, GlaxoSmithKline, Stevenage, United Kingdom, and Upper Merion, PA;
authors.forename: Rickey R
authors.initials: RR
authors.lastname: Reinhardt
authors.affiliation: GSK Research and Development, GlaxoSmithKline, Stevenage, United Kingdom, and Upper Merion, PA;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Appleby
authors.affiliation: Vita-Salute San Raffaele University, Milan, Italy; Hematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, Milan, Italy; and.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; Department of Pediatrics Division of Stem Cell Transplantation and Regenerative Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy;
authors.forename: Alessandro
authors.identifier: 0000-0002-5398-1717
authors.initials: A
authors.lastname: Aiuti
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007223:Infant; D008297:Male; D020127:Recovery of Function; D012190:Retroviridae; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D015996:Survival Rate
chemical_list: D000243:Adenosine Deaminase