Booth, Claire;
Masiuk, Katelyn;
Vazouras, Konstantinos;
Fernandes, Augustine;
Xu-Bayford, Jinhua;
Campo Fernandez, Beatriz;
Roy, Sohini;
... Kohn, Donald B; + view all
(2025)
Long-Term Safety and Efficacy of Gene Therapy for Adenosine Deaminase Deficiency.
New England Journal of Medicine
, 393
(15)
pp. 1486-1497.
10.1056/NEJMoa2502754.
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Abstract
BACKGROUND Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a life-threatening inborn error of immunity for which lentiviral gene therapy has been investigated in clinical trials. METHODS Between 2012 and 2019, we treated patients who had ADA-SCID with busulfan nonmyeloablative conditioning followed by transplantation with autologous CD34+ hematopoietic stem cells transduced ex vivo with a lentiviral vector encoding human ADA. The primary efficacy end points were overall survival and event-free survival (defined as survival free from rescue allogeneic hematopoietic stem-cell transplantation, reinitiation of enzyme-replacement therapy, and additional gene therapy). Secondary end points included no receipt of immunoglobulin-replacement therapy, the presence of protective titers to tetanus or pneumococcal vaccines, and sustained discontinuation of fungal or viral prophylaxis. We now report the long-term results from this cohort representing 474 patient-years of follow-up, with a median follow-up of 7.5 years. RESULTS We treated 62 patients with ADA-SCID in the United States (33 patients) and the United Kingdom (29 patients). Overall survival was 100%, and event-free survival was 95% (59 of 62 patients). All 59 patients who had successful gene-marked engraftment at 6 months have continued not to receive enzyme-replacement therapy and have had stable gene marking, ADA enzyme activity, metabolic detoxification, and immune reconstitution through the last follow-up; 58 of these patients (98%) discontinued IgG replacement therapy and have evidence of a robust response to vaccinations. None of the patients had a leukoproliferative event or clonal expansion. CONCLUSIONS These long-term findings in a large patient cohort show the sustained clinical efficacy and safety of autologous CD34+ hematopoietic stem-cell lentiviral gene therapy for ADA-SCID, indicating that it is a curative treatment.
| Type: | Article |
|---|---|
| Title: | Long-Term Safety and Efficacy of Gene Therapy for Adenosine Deaminase Deficiency |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1056/NEJMoa2502754 |
| Publisher version: | https://doi.org/10.1056/nejmoa2502754 |
| Language: | English |
| Additional information: | © 2025 Author(s), Massachusetts Medical Society. This Author Accepted Manuscript is licensed for use under the CC-BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10220217 |
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