Simple facts
Milestone: First reported death from gene therapy
Date: September 17, 1999
Location: University of Pennsylvania, Philadelphia
WHO: Jesse Gelsinger
26 years ago today, September 17th, a teenager who underwent experimental gene therapy died. His death led to the necessary changes in the clinical trial process, and ultimately spurred skepticism that stopped the field of gene therapy for years.
Approximately 90% of babies, the most severe forms of OTC deficiency, die. However, Gelsinger, who had a mild, “late-onset” disease, reached adulthood by strictly following a low-protein diet and a regimen of 50 tablets a day, reducing the amount of ammonia in the blood and offsetting its effects. Gelsinger was small at his age and experienced a dangerous ammonia crisis when he stopped taking pills, but otherwise he was healthy.
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Gelsinger wanted to help newborns with the disease, so he enrolled in the trial to test the safety of gene therapy aimed at correcting defective OTC genes. This treatment used a weakened form of adenovirus, a type of cold virus, to supply Gelsinger cells with a corrected form of the OTC gene.
Gelsinger flew to the University of Pennsylvania where the exam was being conducted, but on September 13, 1999, the treatment penetrated the arteries. However, by the next day he was yellowed, developed a severe inflammatory response and blood coagulation disorder, and his organs began to fail. He left life support on September 17th around 2:30pm. Investigations reveal that his death was caused by a severe immune response to the virus used to provide treatment.
According to The New York Times, a Food and Drug Administration investigation discovered many issues with Gelsinger’s registration for the trial. First, his liver function was too poor and when he began his exams, the ammonia levels were too high. Second, the team did not disclose to patients that the lab animals had died from higher doses of treatment prior to the trial. Furthermore, other human participants experienced serious side effects. Meanwhile, Chief Investigator Dr. James Wilson owns a share in Genovo, a company that develops therapy, and has earned millions of people profitable if the treatment is successful.
“We don’t know what the impact of these deviations is,” Dr. Kathryn Zone, then director of the FDA’s Center for Biological Evaluation and Research, said the New York Times reported. “But they are important.”
Gelsinger’s father, Paul Gelsinger, has launched an illegal death lawsuit against the political parties involved in the trial. It was ultimately resolved for a private amount.
Gelsinger’s death has resulted in several changes in how gene therapy clinical trials are conducted and the strengthening of informed requirements. All ongoing gene therapy trials at the University of Pennsylvania have been suspended. The FDA has also begun to need greater surveillance of gene therapy trials.
Death cast poles on the field and gene therapy stopped as public and private funds for the approach were exhausted. However, ultimately, advances have been made in understanding the viral vectors used to provide gene therapy, and subsequently the advent of the cut-and-paste gene editing tool CRISPR has repelled the field.
Scientists are currently using gene therapy to treat many rare genetic disorders, including severe immune deficiency and multiple forms of blindness. The first CRISPR-based gene therapy to treat sickle cell anemia by injuring certain genes was approved in January 2024. In 2025, scientists announced that they would use customized CRISPR treatments designed for specific genetic mutations to treat babies with rare and devastating genetic syndromes.
Currently, there are still few approved gene therapy products. Many of these approved therapies use lab-edited cells to return to the body to fight or treat cancer, rather than modifying the genes in the nuclear cells of the patients themselves.
However, the field has come a long way from Gelsinger’s death, and in 2021 scientists successfully treated OTC deficiency using gene therapy.
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