March 12, 2000 (Anaheim, Calif.) -- A prominent researcher who gained national attention last year for studies involving a gene to grow new blood vessels supplying the heart in patients with severely blocked heart arteries says that the deaths of five patients in his trials were promptly reported to federal agencies. The FDA has suspended four of these experiments, led by Jeffrey Isner, MD, until further notice. At the same time, other researchers in this controversial field of study are cautiously optimistic about new studies using the technique and urge continued careful human study.
One of the deaths in the Isner study involved a 59-year-old man who succumbed within 20 hours of receiving a gene treatment for vascular endothelial growth factor 2, or VEGF-2. This so-called 'naked' gene (called that because it doesn't use a virus to carry it to the targeted site) is injected directly into the heart muscle of patients with severe angina, or chest pain, says Isner. He is a professor of medicine and pathology and chief of vascular medicine and cardiovascular research in the division of vascular medicine of St. Elizabeth's Medical Center in Boston.
"This case was immediately reported to the FDA, and in great detail. They reviewed it. They agreed that the death appeared to be related to the patient's own disease, not related to the gene therapy," says Isner, speaking here Sunday at the American College of Cardiology's 49th Annual Scientific Session.
Isner also says that of the four other deaths in the studies, three were getting treated for hardening of the leg arteries, and the other patient was getting a placebo. None, he says, appear treatment-related. In spite of reports to the contrary, Isner says the FDA's hold on his work isn't safety-related; however, he declined to provide specifics.
"I'm not trying to be coy, and I'm not trying to dodge the question," he says. "The FDA makes decisions. They don't ask us whether we agree with them. We simply are obligated to respond to them."
Meanwhile, a source at the National Institutes of Health (NIH) also says that Isner delayed reporting the patient deaths to the research agency as required. Part of the controversy surrounding gene therapy has been failure of the researchers to report adverse events, such as patient deaths, to both the FDA and the NIH. "There has been a tremendous amount of ambiguity about what needs to be reported to the NIH," says Isner. Gene therapy has come under intense scrutiny since the death last year of 18-year-old Jesse Gelsinger as the result of his treatment for a rare liver disorder. Critics that say gene therapy may never achieve its potential for developing new therapies because of concerns over safety and technical issues.
For the first time, Isner released the results of his 30-patient gene therapy trial. After 12 weeks, 70% of the patients had a significant decrease in angina symptoms, and their ability to exercise increased. "We believe that the data to date continue to show that VEGF-2 is a worthy candidate for continued development," says Isner, although he admits that it's too early to determine if new vessel growth -- or angiogenesis -- has actually taken place.
And, in another presentation, researchers discussed data that another growth factor -- fibroblast growth factor (rFGF-2) -- is showing promise in treating patients with advanced heart disease. This protein works on a number of different cells in the body, not just those associated with vessel growth. In a comparison against placebo in 337 patients with severe angina, those receiving the therapy had significant improvements in symptoms and exercise tolerance after 90 days of therapy compared to those taking the placebo. Researcher Michael Simons, of Beth-Israel Deaconess Medical Center in Boston, says that there was a significant difference in improvement between the two groups.
Timothy D. Henry, MD, director of interventional cardiology at Hennepin County Medical Center and an associate professor of medicine at the University of Minnesota in Minneapolis, says that despite the recent controversy over gene therapy, studies employing this technique, as well as those administering growth factors, have promising results in early trials. "It is important to remember that ... [the ability to grow new blood vessels] is a field [of medicine that is] in its infancy ... it's really brand new," he says. "There are a lot of questions still that can only be answered with further study."