Philadelphia—Ten years ago this month the promise of using normal genes to cure hereditary defects crashed and burned, as Jesse Gelsinger, an 18-year-old from Tucson, Ariz., succumbed to multiorgan failure during a gene therapy trial at the University of Pennsylvania. Today the boardroom of the Translational Research Lab at the university is filled with artifacts reminiscent of the trial. Books such as Building Public Trust and Biosafety in the Laboratory sit on the shelves, and “IL-6” and “TNF-α” are scribbled on the whiteboard—abbreviations representing some of the very immune factors that fatally spiraled out of control in Gelsinger’s body.
These allusions to the past aren’t surprising considering how drastically the clinical trial changed gene therapy and, in particular, the career of James M. Wilson, the medical geneticist who headed Penn’s Institute for Human Gene Therapy, where the test took place. The U.S. Food and Drug Administration banned it from conducting human trials, and Wilson left his post at the now defunct institute (but he continued doing research at Penn). He disappeared from the public spotlight until 2005, when the agency announced he could begin clinical trials with a designated monitor but could not lead trials for five years and asked him to write an article about the lessons he has learned. He published it in Molecular Genetics and Metabolism this past April. Since then, he has begun giving university lectures about the importance of exercising caution as a clinical scientist, especially when it comes to stem cells, which today have the cachet once held by gene therapy.
Wilson talks about what happened in 1999 with a quiet deliberateness suggestive of a painful topic. “With what I know now, I wouldn’t have proceeded with the study,” he says in the boardroom, his back facing the whiteboard. In the 1990s scientists such as himself, he explains, were too caught up in the promise of gene therapy to realize that they did not know enough about it to warrant human testing. “We were drawn into the simplicity of the concept. You just put the gene in,” Wilson says.
The trial he conducted tested the safety of a therapy for ornithine transcarbamylase (OTC) deficiency, a rare disorder in which the liver lacks a functional copy of the OTC gene. The defect prevents the body from eliminating ammonia, a toxic breakdown product of protein metabolism. The Penn scientists had engineered a weakened adenovirus, or cold virus, to deliver a normal copy of the OTC gene into the liver.
Seventeen patients had undergone treatment before Gelsinger, who was in the final cohort—the one receiving the highest dose of the therapy. Many scientists, as well as the FDA, have raised questions as to why Gelsinger was being treated, given that several patients in earlier cohorts suffered severe liver reactions. Wilson says that they moved forward because it was “the kind of toxicity we would have expected,” based on their work in animals, and they thought it would be manageable. According to Mark Batshaw, director of the Children’s Research Institute at the Children’s National Medical Center in Washington, D.C., Wilson and the rest of the scientific community had to learn the hard way “that what you’ve learned from animals will not necessarily predict what’s going to happen in humans.” Batshaw was also involved in the 1999 trial.
The FDA questioned the decision to treat Gelsinger for other reasons, too. Just before starting treatment, Gelsinger—who suffered from a mild form of the disease—had high levels of ammonia in his blood, indicating that his liver was not functioning well. But because his levels were within acceptable parameters when he had enrolled in the trial three months earlier, the scientists moved forward anyway. Wilson, who was responsible for the protocol and its compliance, admits now that “the protocol was not written in a way in which there was enough clarity to know when the ammonia had to be what [level], and that was a significant shortcoming.”