Genetics & Molecular · 1990
First Approved Human Gene Therapy (ADA-SCID, Ashanthi DeSilva)
Adenosine deaminase-deficient severe combined immunodeficiency
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 profoundly immunodeficient from birth. Without treatment, most died of infection in early childhood. Enzyme replacement with polyethylene glycol-modified ADA (PEG-ADA) had become available in 1987 and was life-sustaining, but it was 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 gene transfer procedure formally authorized for use in a human patient by the NIH Recombinant DNA Advisory Committee.
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, received the treatment four months later at the NIH, with a similarly ambiguous result. Neither patient achieved the level of immune reconstitution seen after a successful bone marrow transplant.
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. These were the first facts of that kind derived from an authorized human experiment, and they provided a foundation for the broader field.
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 eventually refined using safer self-inactivating retroviral vectors; Strimvelis, using this improved approach, was approved in Europe in 2016. Libmeldy, using a lentiviral vector in hematopoietic stem cells rather than mature T cells, received European approval in 2020 and offers a more durable reconstitution. Ashanthi DeSilva remained alive and in good health decades after her 1990 treatment.
Key People
- W. French Anderson — NIH molecular biologist who led the first approved human gene therapy trial
- Michael Blaese — NIH Clinical Center immunologist and co-investigator on the ADA-SCID gene therapy trial
- Kenneth Culver — NIH pediatric oncologist who performed the cell transduction and infusions
- Ashanthi DeSilva — First patient to receive an approved gene therapy, treated at age four in 1990
- Martin Cline — UCLA researcher whose unauthorized 1980 gene transfer attempt preceded the NIH protocol
Blaese RM, et al. Science. 1995;270(5235):475-480.
Related landmarks
- 1985 · Polymerase Chain Reaction (PCR) (Genetics & Molecular)
- 2001 · Human Genome Project: First Draft Human Genome Sequence (Genetics & Molecular)
- 1978 · Recombinant Human Insulin (synthesis of the gene) (Genetics & Molecular)
- 1977 · Sanger DNA Sequencing (dideoxy chain-termination method) (Genetics & Molecular)