First Approved Human Gene Therapy (ADA-SCID, Ashanthi DeSilva)

Adenosine deaminase deficiency is one of the most severe forms of primary immunodeficiency. Without functional ADA, deoxyadenosine accumulates and is toxic to T lymphocytes, leaving affected children severely immunodeficient from birth. Without treatment, most died of infection in early childhood. Enzyme replacement with polyethylene glycol-modified ADA (PEG-ADA), approved by the FDA as Adagen in March 1990, was life-sustaining but not curative; T-cell function remained below normal and the drug required ongoing injections. Bone marrow transplantation with a matched sibling donor offered a cure but was available to very few patients. By 1990, there was serious scientific and regulatory interest in whether gene transfer could restore normal immune function.

The team at the NIH Clinical Center that pursued the first approved human gene therapy protocol included W. French Anderson, a molecular biologist who had been advocating for gene therapy trials since the early 1980s; Michael Blaese, an immunologist with expertise in ADA-SCID; and Kenneth Culver, a pediatric oncologist who managed the technical aspects of cell transduction and infusion. The protocol used a retroviral vector to introduce a functional ADA gene into T cells isolated from the patient's blood. On September 14, 1990, Ashanthi DeSilva, a four-year-old girl with ADA-SCID, received the first infusion at the NIH. It was the first authorized gene transfer meant to treat a disease; an earlier NIH study had used a marker gene to track infused immune cells in five patients with melanoma.

The clinical outcome was partial and difficult to interpret. Ashanthi's T-cell counts rose and her immune responses improved over the months following treatment, but she continued receiving PEG-ADA enzyme replacement in parallel. The concurrent enzyme therapy confounded any clean assessment of how much the gene therapy itself was contributing. A second patient, Cynthia Cutshall, aged nine, received the treatment at the NIH a few months later; only about 1 percent of her cells took up the gene, but her immune response improved. In the 1995 report, blood T-cell counts had normalized, as had many immune responses.

Despite the mixed efficacy, the trial produced findings that mattered technically. The retrovirally transduced T cells survived in vivo, the inserted ADA gene was expressed, and no serious adverse events from the gene transfer procedure itself were observed. The trial demonstrated that modified autologous cells could be safely reinfused and that gene expression persisted in circulating lymphocytes. Gene treatment ended after two years, but the integrated vector and ADA expression were still detectable in T cells, and the investigators concluded that gene therapy could be a safe and effective addition to treatment for some patients.

The subsequent decades brought both advances and serious setbacks to gene therapy. The death of Jesse Gelsinger in a 1999 adenoviral gene therapy trial for ornithine transcarbamylase deficiency and the development of T-cell leukemia in children enrolled in French X-linked SCID gene therapy trials in the early 2000s slowed regulatory progress substantially. ADA-SCID gene therapy was later redesigned to target blood stem cells: Strimvelis, approved in Europe in 2016, consists of a patient's own CD34+ cells carrying the ADA gene delivered by a retroviral vector. Lentiviral vectors in the same kind of stem cells now treat other inherited diseases, such as metachromatic leukodystrophy with Libmeldy. Three decades after treatment, both of the first two patients were reported to be doing well while continuing conventional therapy for SCID.