In the first study of its kind, researchers show that gene therapy given during angioplasty is safe and improves blood flow to the heart muscle more than angioplasty alone, according to a report in a recent rapid access issue of Circulation: Journal of the American Heart Association. The trial is the first to transfer copies of the gene for vascular endothelial growth factor (VEGF) into the arteries of heart patients during angioplasty. It’s also the first human study that compared two different approaches to inserting the gene into heart cells.
From American Heart Association:Gene therapy during angioplasty improves blood flow
DALLAS, May 14, 2003 ? In the first study of its kind, researchers show that gene therapy given during angioplasty is safe and improves blood flow to the heart muscle more than angioplasty alone, according to a report in a recent rapid access issue of Circulation: Journal of the American Heart Association.
The trial is the first to transfer copies of the gene for vascular endothelial growth factor (VEGF) into the arteries of heart patients during angioplasty. It’s also the first human study that compared two different approaches to inserting the gene into heart cells.
One approach delivered the gene using a disabled virus called an adenovirus, which is modified so it’s unlikely to cause harm.
The other technique wrapped copies of the gene in liposomes, tiny globules made of thin layers of lipids.
“The most important finding is that we were able show that VEGF, when given by an adenovirus, significantly improved perfusion (blood flow) in the wall of the heart,” says senior author Seppo Yl?-Herttuala, M.D., Ph.D., professor of molecular medicine at the University of Kuopio in Finland.
Blood flow improved in all three groups as the result of angioplasty, but it was not significantly different between the patients treated with the VEGF-carrying liposomes and those given placebo.
Another key question in the trial was whether VEGF therapy could reduce the reclosure (restenosis) of arteries opened by angioplasty.
Advances in angioplasty including the use of drug-coated mesh tubes called stents to help keep arteries open, have greatly reduced the incidence of restenosis. Nonetheless, it remains the major complication of angioplasty.
One animal study had suggested that VEGF gene therapy might increase restenosis. However, the researchers found that VEGF treatment had no effect either way.
“It is important to know that it does not make restenosis any worse,” Yl?-Herttuala says. “That means that in serious coronary heart disease, there is a chance to improve perfusion without by-pass surgery or other difficult operations.”
Today’s report is the latest from research that Yl?-Herttuala began in 1993.
An editorial accompanying it suggests that the researchers’ approach, with additional refinement, may further reduce restenosis by reducing damage to the cells lining the heart arteries.
It is “another step toward ameliorating, rather than perturbing the biology of the artery wall as a restenosis prevention strategy,” write Douglas W. Losordo, M.D., the late Jeffrey M. Isner, M.D., and Larry J. Diaz-Sandoval, M.D., of Tufts University School of Medicine.
The Finnish team enrolled 103 patients, ages 38 to 75, in a randomized, double-blinded study conducted at the cardiology centers of the University of Kuopio and the University of Helsinki. All participants underwent angioplasty to open narrowed heart arteries.
Thirty-seven patients received VEGF via the adenovirus, 28 got the VEGF-containing liposomes, and 38 received Ringer’s lactate, a solution of body salts, as a placebo. Neither the treating physicians nor the patients knew who was in which group.
“This is a truly randomized, truly blinded study, and that is important because in gene therapy there has been a very strong placebo effect,” says. “A randomized, blinded trial is the only way you can find out the efficacy of the drug.”
Many previous VEGF trials have occurred in patients undergoing open-heart surgery, in which ethical standards bar the use of a placebo.
VEGF helps new blood vessels develop, a process called angiogenesis. Yl?-Herttuala and his colleagues believe the VEGF caused the growth of tiny vessels called capillaries in the heart wall, which increased its supply of blood. Other clinical trials have indicated this effect.
“We have shown in another clinical trial, in the legs, that VEGF gene therapy clearly increases the blood vessels,” he says. “We could not do that directly in this study because we could not take samples from the heart and count the capillaries.”
As for the ineffectiveness of the other VEGF therapy, “it is well known that the adenovirus is 100 times to 1,000 times more efficient than liposomes” in transferring genes into cells, he adds.
One person who received the adenovirus-based therapy died 20 months after treatment following the rupture of a previously unknown aortic aneurysm, an event unrelated to the treatment. Three patients, two in the liposome group and one in the adenovirus arm, developed cancers.
“Our independent safety monitoring board clearly concluded that it is highly unlikely that these cancers were due to gene therapy,” Yl?-Herttuala says.
Co-authors are Marja Hedman, M.D., Ph.D.; Juha Hartikainen, M.D., Ph.D.; Mikko Syv?nne, M.D. Ph.D.; Joachim Stjernvall, M.D., Ph.D.; Antti Hedman, M.D., Ph.D.; Antti Kivel?, M.D.; Esko Vanninen, M.D., Ph.D.; Hanna Mussalo, M.D.; Esa Kauppila, M.D.; Sakari Simula, M.D. Ph.D.; Outi N?v?nen, Ph.D.; Arto Rantala, M.D.; Keijo Peuhkurinen, M.D., Ph.D.; Markku S. Nieminen, M.D., Ph.D; and Markku Laakso, M.D., Ph.D.
NR03 ? 1082 (Circ/Yl?-Herttuala)