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It Starts with One: Jesse Gelsinger and Biotechnology in Modern Philadelphia

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BIO Media Relations
June 4, 2019

Jesse Gelsinger was an Arizona teenager who loved motorbikes and making people laugh. What makes him a Philadelphia story? A rare disease of the liver.

Patients with ornithine transcarbamylase deficiency (OTCD) lack the enzyme that breaks down ammonia, which occurs naturally when your body breaks down protein. Gelsinger kept his OTC deficiency relatively controlled with a restricted diet and medication, but a more permanent treatment glimmered on the horizon: a gene therapy being tested at the University of Pennsylvania that used a viral vector to introduce the normal gene for the enzyme that breaks down ammonia. On Jesse’s 18th birthday—the study accepted only those who were 18 or older—the Gelsingers boarded a plane to Philadelphia for some preliminary tests.

Gelsinger was approved to participate in the study. On September 13, 1999, an infusion of corrective OTC gene encased in a dose of attenuated cold virus was injected into Gelsinger’s hepatic artery. He tragically died four days later, apparently having suffered a massive immune response triggered by the viral vector to transport the gene into his cells, leading to multiple organ failure and brain death.

Jesse Gelsinger’s death is the first attributed to gene therapy, and the world took notice. Nearly overnight, gene therapy went from a medical breakthrough to a cautionary tale of scientific overreach.

The FDA suspended the Pennsylvania trial, citing a failure to train staff adequately, develop basic operating procedures, and obtain informed consent. The FDA halted the rest of the University of Pennsylvania’s human trials involving gene therapy and began investigating 69 other gene therapy trials under way in the United States. Early in 2000, the FDA and the NIH introduced the Gene Therapy Clinical Trial Monitoring Plan, which required disclosure and clinical monitoring before a trial begins and clarified what events need to be reported. The FDA also adopted a policy forbidding investigators and team members who are directly involved in patient selection, the informed-consent process, or clinical management of a trial from holding financial interest in companies sponsoring the trial.

The memory of what happened to Jesse Gelsinger slowed progress in gene therapy not only for OTCD but for all conditions—until now. Our understanding of physiology and the technologies available to us have advanced enough since 1999 that we can now safely resume experiments with gene therapy in humans.

Philadelphia, a venerable health-care town, is a center of the growing gene therapy manufacturing industry, home to more than a dozen companies developing such therapies. UPenn has expanded its own gene therapy development and manufacturing programs, in partnerships with Novartis and others. The Wistar Institute, Christiana Hospital, Thomas Jefferson University, and other area institutions also work in the field. In 2017 Philadelphia-based Spark Therapeutics received FDA approval for the first-ever gene therapy designed to treat an inherited disease: Luxturna is a one-time treatment for a genetic eye disorder that leads to blindness. In February of this year Roche Holding AG of Switzerland purchased Spark for $4.3 billion.

As Wired wrote, “Viewed one way, Gelsinger’s death nearly destroyed gene therapy. But seen another way, it spurred the field’s scientists to discoveries—a new understanding of the immune system and a new set of viruses to outwit it—that might never have been achieved otherwise.”

Jesse Gelsinger: it starts with one.

Part 3 of this series on the history of biotech in Philadelphia will appear in tomorrow’s show daily.

To learn more about the history of biotechnology, visit the Science History Institute at 315 Chestnut Street while you’re in Philadelphia!  Or visit us online at sciencehistory.org.