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Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency.
Reinhardt, Bryanna; Habib, Omar; Shaw, Kit L; Garabedian, Elizabeth; Carbonaro-Sarracino, Denise A; Terrazas, Dayna; Fernandez, Beatriz Campo; De Oliveira, Satiro; Moore, Theodore B; Ikeda, Alan K; Engel, Barbara C; Podsakoff, Gregory M; Hollis, Roger P; Fernandes, Augustine; Jackson, Connie; Shupien, Sally; Mishra, Suparna; Davila, Alejandra; Mottahedeh, Jack; Vitomirov, Andrej; Meng, Wenzhao; Rosenfeld, Aaron M; Roche, Aoife M; Hokama, Pascha; Reddy, Shantan; Everett, John; Wang, Xiaoyan; Luning Prak, Eline T; Cornetta, Kenneth; Hershfield, Michael S; Sokolic, Robert; De Ravin, Suk See; Malech, Harry L; Bushman, Frederic D; Candotti, Fabio; Kohn, Donald B.
Afiliação
  • Reinhardt B; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Habib O; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Shaw KL; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Garabedian E; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
  • Carbonaro-Sarracino DA; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Terrazas D; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Fernandez BC; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • De Oliveira S; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA.
  • Moore TB; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA.
  • Ikeda AK; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA.
  • Engel BC; Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA.
  • Podsakoff GM; Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA.
  • Hollis RP; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Fernandes A; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Jackson C; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Shupien S; Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA.
  • Mishra S; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Davila A; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Mottahedeh J; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Vitomirov A; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Meng W; Department of Pathology and Laboratory Medicine and.
  • Rosenfeld AM; Department of Pathology and Laboratory Medicine and.
  • Roche AM; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
  • Hokama P; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
  • Reddy S; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
  • Everett J; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
  • Wang X; Department of General Internal Medicine and Health Services Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
  • Luning Prak ET; Department of Pathology and Laboratory Medicine and.
  • Cornetta K; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
  • Hershfield MS; Departments of Medicine and Biochemistry, Duke University School of Medicine, Durham, NC.
  • Sokolic R; Department of Medicine, Alpert Medical School, Brown University, Providence, RI.
  • De Ravin SS; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; and.
  • Malech HL; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; and.
  • Bushman FD; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
  • Candotti F; Division of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
  • Kohn DB; Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Blood ; 138(15): 1304-1316, 2021 10 14.
Article em En | MEDLINE | ID: mdl-33974038
ABSTRACT
Patients lacking functional adenosine deaminase activity have severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy [GT]). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a phase 2 clinical trial between 2009 and 2012. Autologous bone marrow CD34+ cells were transduced ex vivo with the MND (myeloproliferative sarcoma virus, negative control region deleted, dl587rev primer binding site)-ADA gammaretroviral vector (gRV) and infused following busulfan reduced-intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8 to 11 years. Nine of 10 patients have sufficient immune reconstitution to protect against serious infections and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of 9 evaluable patients with the highest gene marking and B-cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34+ cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID but also highlight risks of genotoxicity with gRVs. This trial was registered at www.clinicaltrials.gov as #NCT00794508.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Terapia Genética / Imunodeficiência Combinada Severa / Agamaglobulinemia Tipo de estudo: Clinical_trials / Guideline / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adolescent / Child / Child, preschool / Humans / Infant Idioma: En Revista: Blood Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Canadá
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Terapia Genética / Imunodeficiência Combinada Severa / Agamaglobulinemia Tipo de estudo: Clinical_trials / Guideline / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adolescent / Child / Child, preschool / Humans / Infant Idioma: En Revista: Blood Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Canadá