The death of 18-year-old Jesse Gelsinger in 1999 marked a seminal event in the field of human gene therapy. He was the first person publicly identified to die in a gene-therapy trial in medical history conducted for ornithine transcarbamylase deficiency (OTC).
Ornithine Transcarbamylase Deficiency (OTC deficiency), is a genetic condition, an X-linked metabolic disorder in which the liver cannot properly break down ammonia, a by-product of protein metabolism.
Although most infants with the severe form of OTC deficiency die within few days, Gelsinger had a milder form of genetic mutation (somatic mosaicism) and managed his condition with a strict low-protein diet and medication.
Jesse was described by his family as lively, outspoken and physically active as a child and before the trial. He was interested in motorcycles, wrestling, work, sports and ordinary teenage life, despite living with a mild form of ornithine transcarbamylase deficiency (OTC).
He was not diagnosed with OTC deficiency until almost 3 years of age, when he was put on a high protein diet due to his scrawny physique and to correct a suspected anemia. The high protein diet spiraled him into a coma and after multiple investigations, he was diagnosed with the genetic condition. After that he had a normal upbringing with few episodes of increased ammonia in his system which was managed by medication and few hospital admissions.
His father’s account portrays him as spirited and resilient: he attended school, held a part-time job, resisted illness-related restrictions at times, and recovered from earlier metabolic crises before volunteering for the trial.
The trial at the University of Pennsylvania was an early safety study intended to test whether a viral (adenovirus) vector could deliver a functioning OTC gene, ultimately a step toward treating severe infant cases and it was not designed to provide therapeutic benefit to adult participants. Upon multiple requests from his treating physician whether he wanted to join the trial, he traveled to Philadelphia soon after turning 18 to undergo screening and consent procedures.
Jesse and his family understood the trial’s experimental nature, but he agreed to enroll because he hoped to help advance research that might benefit others with the disorder. The side effects and preclinical trial results disclosed to them were not accurate and would only be discovered after his death.
He volunteered in a phase I gene-therapy trial at the University of Pennsylvania (Penn) under the leadership of Dr. James M. Wilson, director of the Institute for Human Gene Therapy.
Before entering the clinical trial, Jesse Gelsinger underwent a nitrogen-15 (N¹⁵) ammonia challenge test to assess his liver’s ability to process ammonia, the key metabolic function affected in ornithine transcarbamylase deficiency (OTC). The test involved administering a trace amount of labeled ammonia and measuring its conversion to urea. Results indicated that Jesse’s ammonia metabolism was functioning at approximately 6% of normal enzyme efficiency, confirming a partial, non-severe form of OTC deficiency.
This level allowed him to live a stable life with dietary control and medication. Based on these findings, researchers categorized him in the mild OTC group, meaning he was not expected to benefit personally from the experimental gene therapy but would contribute to evaluating its safety, immune response, and vector tolerance.
After receiving the adenoviral vector infusion on September 13, 1999, Jesse Gelsinger experienced a severe systemic inflammatory response within hours. The viral vector, designed to deliver a functional OTC gene to his liver cells, triggered an intense immune reaction involving the rapid release of inflammatory cytokines. This led to fever, severe jaundice and multi-organ failure, including acute liver dysfunction, kidney failure, and lung complications. His ammonia levels kept climbing along with a blood clotting issue and despite aggressive intensive care measures, Jesse’s condition deteriorated rapidly, and he died four days later, on September 17, 1999, from multiple organ system failure due to the immune response to the adenoviral vector.
Subsequent reporting and government reviews found that the informed-consent process and disclosures to participants were incomplete. Investigators did not fully disclose prior serious adverse events from the trial and related preclinical work: earlier human volunteers had experienced significant side effects, and high-dose experiments of injecting ammonia in lab monkeys had resulted in 2 deaths. Jesse Gelsinger's liver was already under stress (ammonia levels high) and the inclusion criteria arguably allowed him to participate despite elevated risk.
The head researcher, Dr. James Wilson had a conflict of interest and had a stake in the biotech company who stood to benefit from the trial. Previous adverse events were not reported to FDA by the team. Regulatory inquiries concluded that these omissions, together with other protocol and reporting lapses, were central concerns in the investigations that followed Jesse’s death. The FDA later cited several violations and the University of Pennsylvania suspended certain research activities while reforms and settlements followed.
Jesse Gelsinger’s death marked a turning point in gene therapy research and clinical ethics. In the months that followed, the U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) launched comprehensive investigations into the conduct of the study at the University of Pennsylvania.
The case led to temporary suspension of several gene therapy trials, stricter Institutional Review Board (IRB) oversight, and a renewed emphasis on transparency in clinical research.
An ethical question that was raised in the Gelsinger case was whether relatively healthy adult volunteers with OTC (such as Gelsinger) should have been used as subjects especially when there were even sicker babies or newborns who might have benefitted from it. But the argument that only adults can consent to a trial and parents of sick babies are not in a state to give consent was morally weak.
The Institutional Review Board (IRB) overseeing the clinical trial for gene therapy later faced scrutiny for inadequate monitoring and for not halting the study despite protocol deviations and unreported adverse events in earlier participants.
It also prompted the development of clearer informed consent requirements and mandatory reporting of adverse events to federal authorities.
These combined factors made the Gelsinger case a landmark for bioethics, human-subject protection and gene-therapy regulation.
What is gene therapy?
Gene therapy is a medical technique that aims to treat or prevent disease by modifying a person’s genetic material. It typically involves inserting a normal copy of a gene into cells to replace a faulty or missing one, often using viral vectors.
What are the ethical issues with gene therapy?
Ethical concerns in gene therapy include ensuring informed consent, managing safety risks, and maintaining transparency in research, equity in access, and addressing the debate over heritable gene editing.
What is OTC deficiency?
Ornithine transcarbamylase (OTC) deficiency is a rare genetic disorder that prevents the body from removing ammonia, a waste product from protein metabolism. It ranges from severe forms in newborns to mild adult cases managed with diet and medication.
Who was Jesse Gelsinger and why is his case important?v
Jesse Gelsinger was an 18-year-old with mild OTC deficiency who died in 1999 after a gene therapy trial. His case exposed key ethical and safety issues in early human genetic research.
References
Gelsinger, Paul. Jesse’s Intent. Tucson, AZ: Paul Gelsinger, 2001. PDF accessed October 30, 2025. https://www.circare.org/submit/jintent.pdf.
“Gene Therapy | Description, Uses, Examples, & Safety Issues.” Encyclopaedia Britannica. Accessed October 30, 2025. https://www.britannica.com/science/gene-therapy.
“Gene Therapy Research & the Case of Jesse Gelsinger.” NYU Langone Health — Medical Ethics Project. Accessed October 30, 2025. https://med.nyu.edu/departments-institutes/population-health/divisions-sections-centers/medical-ethics/education/high-school-bioethics-project/learning-scenarios/jesse-gelsinger-case.
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