Evidence map›Paper›PMID 33974038›Full record

Trial reportBlood2021

Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency.

Bryanna Reinhardt, Omar Habib, Kit L Shaw, Elizabeth Garabedian, Denise A Carbonaro-Sarracino, Dayna Terrazas, Beatriz Campo Fernandez, Satiro De Oliveira, Theodore B Moore, Alan K Ikeda and 26 more

Registry-linked trialOpen access · bronzeAbstract readClinical Trial, Phase II
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Blood, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00794508 (MND-ADA Transduction of CD34+ Cells From the Bone Marrow Of Children With Adenosine Deaminase), which is not on this map. Cited by 27 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed, 1 pooled it
6.9field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT00794508 phase2completednot on this map

MND-ADA Transduction of CD34+ Cells From the Bone Marrow Of Children With Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID): Effect of Discontinuation of PEG-ADA and Marrow Cytoreduction With Busulfan

TypeinterventionalSponsorDonald B. Kohn, M.D.Ran2008 to 2015Enrolled10ConditionsSevere Combined ImmunodeficiencyArmsADA gene transfer
3 · Its place in the literature

Who cites it

27 citing papers in PubMed, 1 synthesis or guideline pooled it, 48 citations in OpenAlex.

  1. Pooled it
  2. Trial
  3. Article
  4. Article
  5. Review
  6. Review
  7. Review
  8. Balancing efficacy and safety in lentiviral vector-mediated hematopoietic stem cell gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025
    Article
  9. Review
  10. Article
  11. Review
  12. Improving access to gene therapy for rare diseases.Disease models & mechanisms · 2024
    Article
  13. Article
  14. Article
  15. Article
  16. Article
  17. Review
  18. Review
  19. Review
  20. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

36 authors at 8 institutions in 2 countries.

Bryanna ReinhardtDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Omar HabibDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Kit L ShawDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.ORCID 0000-0002-1293-8050
Elizabeth GarabedianOffice of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Denise A Carbonaro-SarracinoDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Dayna TerrazasDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Beatriz Campo FernandezDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Satiro De OliveiraDivision of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA.
Theodore B MooreDivision of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA.
Alan K IkedaDivision of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA.
Barbara C EngelResearch Institute, Children's Hospital of Philadelphia, Philadelphia, PA.
Gregory M PodsakoffResearch Institute, Children's Hospital of Philadelphia, Philadelphia, PA.
Roger P HollisDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Augustine FernandesDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Connie JacksonDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Sally ShupienDivision of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA.
Suparna MishraDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Alejandra DavilaDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Jack MottahedehDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Andrej VitomirovDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Wenzhao MengDepartment of Pathology and Laboratory Medicine and.
Aaron M RosenfeldDepartment of Pathology and Laboratory Medicine and.ORCID 0000-0002-2266-0355
Aoife M RocheDepartment of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Pascha HokamaDepartment of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Shantan ReddyDepartment of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
John EverettDepartment of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Xiaoyan WangDepartment of General Internal Medicine and Health Services Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Eline T Luning PrakDepartment of Pathology and Laboratory Medicine and.ORCID 0000-0002-9478-9211
Kenneth CornettaDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
Michael S HershfieldDepartments of Medicine and Biochemistry, Duke University School of Medicine, Durham, NC.
Robert SokolicDepartment of Medicine, Alpert Medical School, Brown University, Providence, RI.ORCID 0000-0002-3399-7893
Suk See De RavinNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; and.ORCID 0000-0002-9800-774X
Harry L MalechNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; and.ORCID 0000-0001-5874-5775
Frederic D BushmanDepartment of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Fabio CandottiDivision of Immunology and Allergy, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.ORCID 0000-0001-6399-6042
Donald B KohnDepartment of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.ORCID 0000-0003-1840-6087
University of California, Los Angeles · USUniversity of Pennsylvania · USNational Institutes of Health · USChildren's Hospital of Philadelphia · USBrown University · USDuke University · USIndiana University School of MedicineUniversity of Lausanne · CH

Funding

UNIVERSITY OF PENNSYLVANIA CAN CTR SUPPORT GRANTP30CA016520 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Robert H. Vonderheide · 1985 to 2026
$222.3M
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1M
Virus & Reservoirs CoreP30AI045008 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI DAVID S METZGER · 1999 to 2026
$78.6M
Gene Therapy Basic Research to Treat Inherited Primary Immune DeficienciesZIAAI000644 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI MALECH, HARRY L · 2009 to 2025
$12.1M
Development and Clinical Application of Gene and Cell therapies for Patients with Immune DeficienciesZIAAI000645 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI DE RAVIN, SUK SEE · 2009 to 2025
$10.1M
National Gene Vector Biorepository and Coordinating Center at Indiana UniversityP40HL116242 · NHLBI · INDIANA UNIVERSITY INDIANAPOLIS · PI CORNETTA, KENNETH · 2012 to 2017
$5.5M
National Gene Vector Biorespository and Coordinating Center at Indiana UniversityP40RR024928 · NCRR · INDIANA UNIVERSITY INDIANAPOLIS · PI CORNETTA, KENNETH · 2008 to 2011
$4.0M
PURPOSE OF THE NGVB CONTRACT IS TO CONTINUE SUPPORTING GENE THERAPY RESEARCH.75N92019D00018 · OD · INDIANA UNIVERSITY INDIANAPOLIS · 2019 to 2023
$1.7M
MND-ADA Transduced CD34 Cells for ADA-SCIDR01FD003005 · FDA · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI KOHN, DONALD B · 2005 to 2011
$881k
REGULATION OF THE BIOSYNTHESIS OF THE OPIOID PEPTIDES AND OTHER NEUROPEPTIDESZ01HL000018 · NHLBI · HEART, LUNG, AND BLOOD INSTITUTE · PI SABOL, S L · 1985 to 1992
–
FDA HHS R01 FD003005NCI NIH HHS P30 CA016520NCRR NIH HHS P40 RR024928NHLBI NIH HHS 75N92019D00018NHLBI NIH HHS P40 HL116242NIAID NIH HHS P30 AI045008
6 · The paper itself

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.

Indexed as

Genetic TherapyAdenosine DeaminaseAdolescentAgammaglobulinemiaChildChild, PreschoolFollow-Up StudiesHematopoietic Stem Cell TransplantationHumansInfantSevere Combined ImmunodeficiencyTransplantation, AutologousTreatment OutcomeADA protein, humanAdenosine Deaminase

Identifiers

PMID33974038
PMCPMC8525336
OpenAlexW3161875586

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.