Takeaways
- Lentiviral gene therapy for ADA-SCID demonstrated 100% overall survival and 95% event-free survival, with durable engraftment and no late treatment failures beyond 1 year.
- Immune reconstitution remained robust long term, with sustained T-cell, B-cell, and NK-cell recovery, and 98% of patients successfully discontinuing immunoglobulin-replacement therapy.
- No vector-related safety events were observed, including no leukoproliferative complications or dominant clonal expansions, supporting a strong long-term safety profile.
Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency is a life-threatening inherited disorder characterized by toxic metabolite accumulation, profound lymphopenia, and recurrent severe infections.1 Without treatment, life expectancy is less than 2 years. Long-term clinical outcomes from a multicenter cohort treated with autologous CD34+ hematopoietic stem cells transduced with a self-inactivating lentiviral vector have now been reported, representing 474 patient-years of follow-up.2
What were the long-term survival and event-free outcomes in ADA-SCID?
A total of 62 patients with ADA-SCID received autologous lentiviral gene therapy following busulfan nonmyeloablative conditioning. Patients were followed for a median of 7.5 years (range, 5.0–11.2). Overall survival was 100%, and event-free survival was 95%. Event-free survival was defined as survival without reinstitution of enzyme-replacement therapy, rescue allogeneic hematopoietic stem-cell transplantation, or additional gene therapy.
Three patients experienced early treatment failure by 6 months, all marked by absent or declining gene marking. Two patients underwent rescue allogeneic transplantation, and one continued enzyme- and immunoglobulin-replacement therapy while awaiting transplantation. No treatment failures were recorded beyond 1 year.
How durable was gene marking and metabolic correction after lentiviral gene therapy?
Among the 59 patients with successful engraftment, gene marking remained stable throughout follow-up. Granulocyte vector copy numbers observed at 3 months remained consistent over time, supporting durable engraftment of corrected long-term hematopoietic stem cells.
All engrafted patients demonstrated sustained metabolic detoxification, with complete absence of toxic adenine metabolites. ADA enzyme activity remained within or above normal ranges. The study reported “an absence of toxic metabolites,” reinforcing the stability of biochemical correction.
How robust was immune reconstitution after treatment?
Lymphocyte reconstitution was durable across T-cell, B-cell, and natural killer cell subsets. CD3+ T-cell counts remained above 1000 cells/µL, and CD4+ T-cell counts stabilized within age-appropriate reference ranges. Naive T-cell populations persisted in all engrafted patients, and T-cell receptor excision circle levels supported continuous thymic output throughout long-term follow-up.
B-cell recovery supported stable immunoglobulin production. Immunoglobulin-replacement therapy was discontinued in 98% of engrafted patients, with discontinuation occurring by 37 months in the United Kingdom and by 43 months in the United States. The study noted that “protective tetanus antibody levels were observed in 100% of the vaccinated patients,” indicating strong functional humoral immunity.
Were there any vector-related safety concerns with lentiviral gene therapy?
Across the entire cohort, no leukoproliferative events, no clinically relevant clonal expansion, and no replication-competent lentivirus were observed. Integration-site profiling showed benign, polyclonal patterns without dominant clones. The investigators reported “no leukoproliferative or myelodysplastic complications” related to treatment.
Adverse events were mild to moderate and unrelated to the gene therapy product. Most were consistent with common childhood infections. A small number of serious infections occurred more than 3 years after treatment and resolved without long-term consequences.
How does lentiviral gene therapy compare with allogeneic HSCT for ADA-SCID?
Allogeneic hematopoietic stem-cell transplantation remains a standard treatment for ADA-SCID, but carries inherent risks of alloreactivity, graft-versus-host disease, and complications related to prolonged immunosuppression.
In contrast, autologous lentiviral gene therapy avoids alloreactivity and requires substantially lower busulfan exposure—approximately 70% less than typical HSCT regimens. This reduction may decrease long-term chemotherapy-related risks, including infertility and secondary malignancies. The study noted that autologous therapy “eliminates any complications related to alloreactivity.”
What are the broader implications for treatment of ADA-SCID?
The investigators concluded that the long-term data “show the sustained clinical efficacy and safety” of lentiviral gene therapy for ADA-SCID. Despite manufacturing and commercialization challenges due to the ultrarare nature of the disease, the results support the therapy as a curative option with consistent, durable outcomes.
Efforts to expand access include exploration of scalable manufacturing processes and alternative funding pathways.
References
- Hirschhorn R. Adenosine deaminase deficiency: molecular basis and recent developments. Clin Immunol Immunopathol 1995; 76: Suppl 3: S219-S227.
- Booth C, Masiuk K, Vazouras K, et al. Long-Term Safety and Efficacy of Gene Therapy for Adenosine Deaminase Deficiency. New England Journal of Medicine. 2025;393(15):1486-1497. doi:https://doi.org/10.1056/nejmoa2502754
