Long-Term Safety and Efficacy of Gene Therapy for Adenosine Deaminase Deficiency.
Publication Year:
2025
PubMed ID:
41092330
Funding Grants:
Public Summary:
Adenosine deaminase–deficient severe combined immunodeficiency (ADA-SCID) is a rare genetic disorder that leaves infants and young children without a functioning immune system. Without effective treatment, children with ADA-SCID are at high risk for life-threatening infections. Gene therapy offers a promising alternative to lifelong enzyme replacement or stem-cell transplantation from a matched donor.
In this long-term study, researchers evaluated the safety and effectiveness of autologous gene therapy for ADA-SCID, in which a patient’s own blood-forming stem cells are corrected with a functional ADA gene and returned to the body. The analysis included patients treated across multiple clinical trials, with follow-up now extending more than a decade for many participants.
The study found that gene therapy provided durable and sustained immune reconstitution in the vast majority of treated individuals. Most patients were able to discontinue enzyme replacement therapy permanently and developed robust, functional immune systems capable of protecting them from serious infections. Importantly, no cases of leukemia or other vector-related cancers were observed over long-term follow-up, supporting the continued safety of this approach.
These results demonstrate that autologous gene therapy is a safe, effective, and lasting treatment for ADA-SCID. The findings reinforce gene therapy as a transformative option that can restore immunity, improve quality of life, and offer children with ADA-SCID the possibility of a healthy future.
Scientific 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. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT04049084.).
