When 18-year-old Jesse Gelsinger died September 17, 1999, while participating in a trial of gene therapy at the University of Pennsylvania Institute for Human Gene Therapy, his body responded to the introduction of a gene with an adenoviral vector in a totally unexpected and devastating way. However, the resulting firestorm of controversy, regulatory action, and headlines could have been predicted.
The university halted the study voluntarily, although Mr Gelsinger was the next-to-last patient scheduled to undergo the treatment for the rare metabolic disease caused by a defect in the gene that causes cells to make ornithine transcarbamylase, an enzyme necessary to normal metabolism of protein. In January, the US Food and Drug Administration (FDA) put a hold on the trial, which was a controversial study that used people who were not deathly ill to determine if a gene therapy for the disease was possible. Mr Gelsinger’s inclusion in the study was also questionable because of his youth and because he suffered from a less severe form of the disease that seemed to have resulted from a different gene mutation than the disease that puts infants into a coma 72 hours after birth and usually kills them soon after.
Until Jesse Gelsinger died, the most potent criticism of gene therapy was that it had proved of so little benefit thus far. Even the first trial in 2 girls who suffered from a form of severe combined immune deficiency was tainted because the pair continued to receive injections of peg-ADA, the synthesized replacement for the substance their bodies could not produce (Science. 1995;270:475–480). Now that there has been a death that seems almost certainly related to the treatment itself, gene therapy critics have began to warn that the procedure itself is dangerous.
In a letter to Ruth Kirschtein, MD, the interim director of the National Institutes of Health (NIH), US Representative Henry Waxman, D-Calif, complained of the lack of oversight by the agency over gene therapy trials (http://www.house. gov/waxman). Pointing to the >600 adverse reaction reports that poured into the agency after it requested such information, he wrote: “The sheer volume and variety of noncompliance with the NIH guidelines evident in gene therapy serious adverse event data is extremely troubling in itself. It underscores, however, the absolute need not only for federal regulation, but for federal regulation that is competent and comprehensive.”
However, the Recombinant DNA Advisory Committee (RAC), the NIH’s most potent weapon for approving and overseeing gene therapy, was stripped of most of its authority in 1995 after an expert panel found that its regulatory authority duplicated that invested in the FDA. Harold Varmus, MD, the immediate past director of the NIH, changed the way gene therapy protocols were approved and took the RAC out of most of the process. More important, he changed the forum of approval for most gene therapy protocols. The RAC debated in open; the FDA considers much information from companies proprietary.
Those who had reported adverse events in the wake of the Gelsinger death became subjects of investigation. A protocol at St Jude’s Children’s Research Center was put on hold. However, subsequent testing allayed fears that the vector itself might be tainted. One of the most high-profile cardiovascular gene therapy trials was halted by the FDA for reasons that have yet to be specified. The man running this trial, Jeffrey Isner, MD, a researcher at St Elizabeth’s Medical Center in Boston whose attempts to use gene therapy to prompt the growth of blood vessels in the legs and hearts of individuals for whom no other therapy was possible, is still bemused by the FDA action.
“One thing that is clear is that putting us on hold had nothing to do with safety issues, death, or reporting,” he said. Although some news reports inferred that reporting had something to do with the FDA shutdown, Dr Isner noted that “we reported everything to the FDA that we were obligated to report to the FDA, and they know for sure that the FDA is not going to put us on clinical hold failure to report something to the NIH.”
He was not surprised that many people had not reported adverse events in their studies to the NIH agency because the situation had become unclear after Dr Varmus changed the status of the RAC. Dr Isner noted that many, if not most, researchers, thought that reporting adverse events to the FDA was sufficient. “There is no reporting issue here,” he said.
As for safety, Dr Isner makes no excuses for his study, in which all the patients had serious disease. “I am proud as hell of it. The likelihood of taking 80-some patients in class III or class IV angina who were not candidates for angioplasty or bypass and getting through a year or 2 years of follow-up with only 2 deaths—I don’t think we can do it again. If they expect any better record, everyone should pack it in.”
He said the one thing that has been asked for are the blood levels of vascular endothelial growth factor (VEGF) in the patients who received the substance. He said he and his group have been working to develop an assay for that, but “in the absence of a significant safety issue, it’s not a basis for putting a company on hold.”
Dr Isner and Vascular Genetics, Inc, had completed enrollment and dosing in 3 of its clinical trials—one for the treatment of coronary artery disease and 2 trials for the treatment of critical limb ischemia. However, a fourth trial meant be a double-blind, placebo-controlled, dose-response study of the catheter-based delivery of VEGF-2 for coronary artery disease had completed most, but not all, of its enrollment target.
In its December meeting, the RAC held public hearings in which the University of Pennsylvania researcher, Dr James M. Wilson, defended his protocol and admitted to some errors in the study in which Jesse Gelsinger was involved. At its most recent meeting in March, the meeting bogged down in minutiae as committee members dissected a proposal for the better reporting of adverse events. The issue will not be taken up again until the group reconvenes in June.
Why Jesse Gelsinger died remains the unanswered question. Was he unsuitable for the study? Were his ammonia levels too high? Did the adenoviral vector evoke an overwhelming immune response? The RAC did not want the vector administered into an artery that led to the liver, but the FDA approved the trial on the condition that the study be performed in that manner only, and not by intravenous infusion, as the RAC preferred. Because the RAC did not meet for the year during which the FDA approved the change in protocol, it could not make recommendations on that matter.
The promise of gene therapy as a treatment for diseases resulting from a single gene defect and for those that result from a cascade of misspelled DNA remains, but the current controversy presents a barrier.
In an editorial, Savio Woo, PhD, the President of the American Society of Gene Therapy and a professor at the Mt Sinai School of Medicine in New York City, and Inder Verma, PhD, president-elect of the American Society of Gene Therapy and a professor of genetics at The Salk Institute in La Jolla, Calif, wrote: “Increased scrutiny of gene therapy trials is called for. Researchers should immediately report serious adverse events in trial patients to the federal agencies overseeing gene therapy trials according to their rules and guidelines. That will be a means where any pattern of problem can be discovered and then shared with all of the investigators conducting trials, as well as with the public” (http://www.asgt.org/press_releases/022800.html).
The editorial further noted: “Researchers also have another area that must be openly and honestly dealt with: potential conflicts of interest between profit pressures and the pursuit of progress in clinical trials. This is new territory that encompasses many different areas of clinical research in addition to gene therapy today and must be carefully navigated.”
It has been >10 years since genetic engineering gadfly Jeremy Rifkin appeared before the RAC. At that time, he warned the group about the potential serious health risks of using viral vectors in the first human trial of somatic gene therapy. In March, he once again appeared before the committee. He said, “Now, a decade later, we face the grim reality of several unaccounted for deaths and the reporting of hundreds of adverse events using adenoviral vectors. In addition, researchers have failed to disclose vital information to government agencies, and biotech companies have hidden behind the veil of trade secrets, patent protection, and proprietary information. In the same 10-year period, >300 separate experiments involving thousands of patients have yet to result in a single cure.”
Calling gene therapy a “field of research that’s run amok,” Rifkin called for an immediate moratorium on the continuation of any somatic gene therapy trials using adeno, retro, or other viral vectors, except as a last resort in cases of life and death. Because very few trials are now involved in tests of efficacy, he said that research could continue without placing “nonterminal” patients at risk of adverse effects. He then proposed a slow phase-in if tests show that the treatment is safe and nontoxic. “Even one more unnecessary death in these gene therapy trials is one death too many,” he said (http://www.biotechcentury.org/breaking.html).
Members of the RAC and its audience spoke against the proposal, and the group took no action on it. However, ignoring the issues raised by Mr Gelsinger’s death will not be possible in the future.
- Copyright © 2000 by American Heart Association