DALLAS, August 3 -- The first human test of a gene therapy that is injected directly into the oxygen-starved heart muscle has shown the technique to be safe, opening the door to promising new treatments for heart disease, according to a report in today's Circulation: Journal of the American Heart Association.
"The implications are huge. To say anything less than that is an understatement. This addresses a tremendous problem of the large number of very sick patients for whom we can do nothing to help their coronary artery disease," says the study's lead author Todd K. Rosengart, M.D., associate professor of cardiothoracic surgery at Weill Medical College of Cornell University, New York City.
The study found no evidence that either the gene or the method used to deliver it (an inactive virus) caused any adverse side effects. "There is no evidence of inflammation, damage to the heart muscle, or viral effects," says Rosengart.
The small, preliminary study of 21 heart patients was not designed to prove the gene therapy's effectiveness. That will require further research, including clinical trials with large numbers of patients.
A build-up of fatty deposits in heart arteries reduces the flow of blood and can lead to a heart attack. Although the Cornell study was not designed to look at gene therapy's role in treating heart disease, most participants said they experienced less chest pain after the injection. A variety of tests also found that the injection led to a growth of new blood vessels, thereby improving blood flow to oxygen-starved areas of their hearts.
"We don't have enough patients to say anything definite about the effectiveness of this therapy in treating heart disease, but if you look at the trends in the data, they are all in the right direction, which is very encouraging," says Ronald G. Crystal, M.D., professor of medicine and chief of pulmonary and critical care medicine also at Cornell University. "If this works, it has the potential to become a major weapon for the treatment of heart disease."
The study emerged from collaboration between the two researchers that began four years ago. Rosengart is interested in angiogenesis, the growth of blood vessels in the body. Crystal is a pioneer in gene therapy. Together they developed a way to deliver a gene that stimulates blood vessel growth -- the vascular endothelial growth factor (VEGF) gene -- to heart cells. The gene is active during fetal development and then essentially turns off in the heart. The researchers used an adenovirus, a cause of the common cold, to deliver the VEGF gene. The virus was modified so that it could not reproduce itself.
Crystal says adenoviruses have several advantages as delivery agents, because for every two viruses put on a cell's surface, one of them will make it to the nucleus and deliver the gene.
Both bypass surgery, which routes blood around a blocked section of an artery, and angioplasty, in which a balloon is inflated inside a clogged artery to open the vessel, are effective treatments for coronary heart disease. However, many patients cannot be helped by either procedure because their disease is too severe or too widespread. "So this research arose out of a very large problem," Rosengart says.
Crystal compared the gene therapy to a road crew building just enough new roads to move traffic around a blocked highway. "What we're doing is sending in a biological work crew for about a week to make new highways that go around the obstruction," he explains. "Once we've made the new highways -- the new coronary arteries -- the work crew is not needed and goes away."
The Cornell team treated 15 patients (11 men, 4 women) undergoing bypass surgery with the gene therapy and another six patients (four men, two women) who had gene therapy as their only treatment. The patients received 10 injections into the heart muscle in an area surrounding a blocked artery that measured about 50 square centimeters, or roughly the surface area of a chicken egg.
Prior to and 30 days after doing an operation, the researchers assessed each patient's level of chest pain (angina), the size of the heart area receiving insufficient blood, the patient's response to exercise on a treadmill, and the amount of motion in the diseased area of the heart wall.
Three of the 15 patients who underwent bypass surgery died within 145 days of their operations. None of the deaths resulted from the gene therapy. There were no deaths among the six patients who received gene therapy as their sole treatment.
Most patients from both groups reported less chest pain after their treatment. Tests also showed evidence of new vessel growth, improved blood flow to the heart muscle, and improved heart wall functioning.
If further research proves that the gene therapy is effective, it could be used in several ways to treat coronary heart disease researchers say.
"Cardiac surgeons could use it in addition to bypass surgery," Crystal says. "Invasive cardiologists might use it with, or instead of, angioplasty. Finally, it could be used alone, as we did with six patients."
Co-authors are Leonard Y. Lee, M.D.; Shailen R. Patel, M.D.; Timothy A. Sanborn, M.D.; Manish Parikh, M.D.; Geoffrey W. Bergman, M.B.B.S.; Rory Hachamovitch, M.D.; Massimiliano Szulc, Ph.D.; Paul D. Kligfield, M.D.; Peter M. Okin, M.D.; Rebecca T. Hahn, M.D.; Richard B. Devereux, M.D.; Martin R. Post, M.D.; Neil R. Hackett, Ph.D.; Taliba Foster, M.S.; Tina M. Grasso, B.S.; Martin L. Lesser, Ph.D.; and O. Wayne Isom, M.D.