Orkin and Motulsky reported in December, at length and scathingly. The promise of gene therapy appeared great, but its failures had persisted despite the RAC’s approval of more than a hundred protocols. Most clinical trials were too small and exploratory in nature to evaluate the medical merits of the treatment; they lacked adequate controls and rigorously stated goals. Gene therapy, the panelists concluded, had been widely and harmfully oversold.
The balloon was pricked. The RAC had been considering approximately 15 protocols at each of its regular sessions; but the next meeting, scheduled for March 1996, was canceled. No proposals requiring public review had been submitted.
Three years later came Jesse Gelsinger’s death.
Gelsinger and the 17 other patients in the trial at the University of Pennsylvania were being treated for a deficiency of the enzyme ornithine transcarbamylase, which the liver uses to break down ammonia, a by-product of protein digestion, into harmless waste products. In its most severe form, the deficiency kills babies in their first year. Gelsinger had been kept alive on a strict diet and a regime of pills. When he learned of the gene-therapy trial, he volunteered.
The trial was carried out at the university’s Institute for Human Gene Therapy, which was headed by James Wilson. It was one of the top such centers in the country. The corrective gene was loaded into an adenovirus. The 18 patients were divided into groups that got increasingly large doses. Gelsinger got the biggest–a culture of 38 trillion virus particles. He received the dose on September 13, 1999. By September 15, his vital signs were falling precipitously. With his father’s assent, he was taken off life support, and he died on September 17.
Jesse Gelsinger’s death was the first directly attributed to gene therapy. An alert went out to the hundred or so experimenters using adenovirus vectors. In the press and in scientific journals, the case was reported as a disaster for the field.
NIH investigated and called a special public meeting for December 8, 9, and 10. The problem became clearer. The protocol for the trials, as approved four years earlier by the RAC and the FDA, had called for the adenovirus vector to be injected intravenously. The FDA had subsequently authorized direct injection of the vector into the hepatic artery, which was the method actually used. Nonetheless, Gelsinger’s autopsy found that the vector was widespread in his spleen, lymph nodes, and bone marrow.
Meanwhile, the FDA was conducting its own inquiry. Investigators were harshly condemnatory. Selection of trial participants had been sloppy at best: Wilson and his colleagues were unable to produce proof that any of the volunteers had met the criteria for the trials. Informed-consent procedures had been grossly inadequate. Federal rules require that benefits and risks be explained fully and clearly; Paul Gelsinger, Jesse’s father, told the New York Times that the family had been led to think the treatment might help Jesse, though the trial had been designed only to test the safety of a treatment being developed for infants. Further, the consent form had failed to mention that monkeys had died after a similar though stronger treatment. In 1992 Wilson had founded a private research company, Genovo, in which he held stock. The company had not put money into this particular study, but it did contribute a healthy portion of the Institute for Human Gene Therapy’s overall budget.