Gene Therapy Shows Durable Safety and Efficacy in ADA‑SCID: 7.5­‑Year Follow-up in 62 Patients

In a landmark long‑term follow-up study published in the New England Journal of Medicine, Booth et al. report that autologous lentiviral gene therapy for adenosine deaminase–deficient severe combined immunodeficiency (ADA‑SCID) demonstrates sustained clinical benefit and an excellent safety profile over a median of 7.5 years (474 total patient‑years) of observation.

ADA deficiency is a rare but severe inborn error of immunity. Infants with ADA‑SCID lack functional immune systems, leaving them vulnerable to life‑threatening infections. Traditional treatments include enzyme replacement therapy (ERT) or hematopoietic stem cell transplantation (HSCT). Gene therapy, which corrects patients’ own stem cells ex vivo using viral vectors, offers a potential “one‑shot” curative approach without needing a donor graft.

From 2012 to 2019, the investigators treated 62 patients across the U.S. (33) and the U.K. (29). Patients first received nonmyeloablative busulfan conditioning, then infusion of autologous CD34⁺ hematopoietic stem cells transduced with a lentiviral vector encoding human ADA. The trial’s primary endpoints were overall survival and event‑free survival (i.e., no need for rescue HSCT, reinitiation of ERT, or additional gene therapy).

The results are striking. Overall survival was 100% at last follow-up, and event-free survival reached 95% (59 of 62 patients). All 59 patients who achieved gene-marked engraftment by 6 months continued to maintain:

• stable vector marking over time

• sustained ADA enzyme activity

• metabolic detoxification

• immune reconstitution

Moreover, 58 of those 59 patients (98%) discontinued immunoglobulin (IgG) replacement therapy, and nearly all mounted protective responses to vaccines. Importantly, none of the participants developed leukoproliferative disease or evidence of clonal expansion.

The authors interpret these findings as evidence that lentiviral gene therapy in ADA‑SCID can be curative, with a favorable long-term risk-to-benefit balance. Their data provide strong support for the durability and safety of this strategy in a historically challenging disease.

This work represents one of the most extensive long‑term gene therapy cohorts yet reported in primary immunodeficiency. It builds on prior shorter-term and smaller-scale studies while addressing the critical question of long-term risks such as insertional mutagenesis or loss of therapeutic benefit.

Nonetheless, even this positive outcome warrants ongoing vigilance. The study design and patient population (e.g. early engrafters) may not capture all rare complications, and continuous monitoring will be essential as more patients are treated and longer durations are reached.