Lentiviral Gene Therapy for Adenosine Deaminase Deficiency

Source: Booth C, Masiuk K, Vazouras K, et al. Long-term safety and efficacy of gene therapy for adenosine deaminase deficiency. N Engl J Med. 2025;393(15):1486-1497; doi: 10.1056/NEJMoa2502754Investigators from multiple institutions conducted a long-term follow-up study of children with severe combined immune deficiency (SCID) due to adenosine deaminase (ADA) deficiency (ADASCID) who were treated with autologous human stem cell transplantation (HSCT) after lentiviral-mediated gene therapy. For the study, children with ADA-SCID, treated with gene therapy between 2012 and 2019 in the US or United Kingdom (UK), were included. Prior to gene therapy, treatment included ADA enzyme replacement and immunoglobulin-replacement treatment. For their HSCT, stem cells were obtained from the bone marrow or peripheral blood of study children and treated with gene therapy using a self-inactivating lentiviral vector for which sections containing oncogenes had been removed. The treated stem cells were then administered back to the patient. The primary study outcome was event-free survival at last follow-up, with events defined as reinstitution of enzyme replacement therapy, rescue allogeneic HSCG, or additional gene therapy. Secondary endpoints included need for continued immunoglobulin therapy and protective titers to tetanus vaccine antigens. Safety endpoints also were assessed.Data were analyzed on 62 children, including 50 who had been enrolled in previous studies. The median age at treatment was 10 months for 33 participants in the US and 14 months for 29 treated in the UK. Among patients in the US, 23 (70%) had been identified via newborn screening. All 62 children were alive at the last follow-up (minimum follow-up 5 years, median follow-up 7.5 years), and 59 (95%) were alive and event-free. Two patients required allogeneic HSCT, and 1 was receiving enzyme-replacement therapy at the time of last follow-up. Of the 59 patients with successful gene therapy, 58 did not require immunoglobulin treatment at the time of last follow-up, and 100% of those vaccinated had protective antibodies to tetanus vaccine antigens. In terms of safety, no leukoproliferative or myelodysplastic complications have occurred in any participants. Infections have occurred, but have resolved, and were caused by typical pediatric pathogens.The authors conclude that children with ADA-SCID, treated with lentiviral therapy, had sustained clinical efficacy over a minimum of 5 years of follow-up, suggesting that it is a curative treatment.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.ADA deficiency is an autosomal recessive, systemic purine metabolic disorder causing pan-lymphocyte dysfunction in addition to non-infectious neurodevelopmental, gastrointestinal, pulmonary, and dermatologic complications.1 ADA deficiency overall comprises 10% to 15% of all SCID cases in the US, with a prevalence of 1 in 500,000 live births.2 Early onset, life-threatening ADASCID accounts for 80% of individuals diagnosed in infancy, compared to 15% to 20% presenting with a less severe, late-onset form in adolescence and adulthood.1Although developed in 2005, newborn screening for ADA-SCID was not fully implemented in all 50 states of the US until 2020.3 Early detection by newborn screening improved overall survival, especially in those <3.5 months of age without active infection at the time of HSCT, a curative therapy.3 Prior to HSCT, affected infants must avoid live viral vaccines, cytomegalovirus-positive breast milk, and exposure to infected individuals.1 Enzyme replacement therapy with pegylated-ADA serves as a bridge to HSCT, because used alone, immune function declines over time.1Improvements in allogeneic HSCT have increased event-free survival to greater than 70%.4 To avoid graft vs host disease and chronic immunosuppression, infusion of ex-vivo, gammaretroviral mediated gene therapy of autologous HSCs has shown long-term efficacy. (See AAP Grand Rounds. 2022;47[2]:22.)5 However, insertional oncogenesis was demonstrated in 1 patient, making it an ongoing risk.6The current researchers report long-term follow-up of their previously published, non-randomized, open-label, phase 1–2 clinical trial of infusion of autologous HSC genetically modified with a self-inactivating ADA lentiviral vector demonstrating >95% event-free survival at 2–3-year follow-up.7 Although manufacturing processes, cell sources, and final drug-product formulation differed among the 3 trials in the US and UK, similar outcomes were observed as in this longer follow-up.7 Other organ toxicities not related to infection were not evaluated in this study.1,2 The involved institutions are working on affordable access and commercial availability for this curative therapy.Most children diagnosed with ADA-SCID who were treated with autologous HSC lentiviral gene therapy demonstrate life-saving immune reconstitution at >5 years of follow-up.