Long-Term Follow-up of Hematopoietic Stem-Cell Gene Therapy for Adenosine Deaminase Deficiency

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Introduction Ex vivo lentiviral hematopoietic stem cell (HSC) gene therapy may offer a curative approach for severe primary immunodeficiencies like severe combined immunodeficiency caused by adenosine deaminase (ADA) deficiency (ADA-SCID). Objective Evaluate the durability of gene marking, immune reconstitution, and clinical outcomes in ADA-SCID patients treated with ex vivo lentiviral HSC gene therapy. Methods We present long-term data (median follow-up = 7.5 years) from an analysis of 61 ADA-SCID patients treated with autologous ex vivo HSC gene therapy, representing 467 patient-years of follow-up. Patients received reduced-intensity busulfan conditioning followed by autologous CD34+ HSCs transduced with a lentiviral vector encoding human ADA ("UCL/A-ADA"). Results Overall survival was 100% (61/61), and event-free survival was 95% (58/61), reflecting survival without reinstatement of enzyme replacement therapy (ERT) or rescue allogeneic HSCT. Adverse events were consistent with the known safety profile of busulfan. No cases of monoclonal expansion, leukoproliferation, replication-competent lentivirus, or deaths occurred. 58 of 61 patients achieved sustained multilineage engraftment of gene-corrected cells. Median granulocyte vector copy number (VCN) remained stable at ∼0.2, indicating durable modification of ∼20% of engrafted HSCs. In PBMCs, with selective advantage for gene-corrected cells, VCN increased from ∼0.5 at month 3 to ∼1.0 at month 36, remaining stable between VCN 0.2-2.0 through last follow-up. Normalization of ADA enzyme activity and metabolic detoxification were achieved within 3 months post-treatment and sustained through last follow-up. T cell counts nadired at month 3 following conditioning and withdrawal of ERT and increased starting at 6 months. Normal T cell counts were achieved by 24 months and remained stable for up to 11 years. Restoration of B cell function was reflected by increased serum IgM and IgA levels to within normal limits over time. Among the 58 patients with successful transplants, 56 discontinued immunoglobulin-replacement therapy at a median of 12.4 months with maintenance of IgG levels in normal range after cessation. 24 of 24 (100%) of evaluable patients had protective (>0.15 IU/mL) anti-tetanus titers. Integration site analysis performed at last follow-up showed polyclonal engraftment, with no clone accounting for more than 2.5% of total integrations. Conclusion Autologous gene therapy with UCL/A-ADA demonstrates safe and sustained immune restoration in ADA-SCID patients. These data represent the largest patient cohort demonstrating long-term safety and efficacy of ex vivo HSC gene therapy.

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