The theory behind VEGF gene therapy is that injecting the gene into the heart will trigger the growth of new blood vessels to nourish oxygen-starved heart muscle.
In both studies, a majority of the surviving patients reported less severe angina, or chest pain, and increased ability to function in their daily lives.
"I'm very comfortable saying this gene therapy is definitely safe. There has never been a complication from the gene itself," says Richard A. Schatz, M.D., director of cardiovascular interventions at Scripps Clinic in San Diego, Calif., and senior author of the VEGF-2 report.
Patients in both studies had end-stage coronary heart disease, suffered disabling angina, and were at high risk of death at any time. None of them could be helped by procedures such as bypass surgery or balloon angioplasty.
Neither trial was randomized nor used a placebo group for comparison.
In the first study presented, Peter R. Vale, M.D. and his colleagues reported results of a trial at St. Elizabeth's Hospital in Boston in which 30 patients aged 48 to 74 (23 men and seven women) were treated with VEGF-1. Patients were followed for 24 to 38 months. There were two deaths: one at five months and one at 28 months after receiving VEGF therapy.
In Vale's study, more than 24 months after receiving the gene therapy, 27 out of 30 patients reported fewer angina episodes per week, from 56 per week to about four per week. They also reported taking fewer nitroglycerin tablets (a treatment for angina) per week - from 60 per week to about three per week.
"Most of our patients also have had a continued improvement in exercise tolerance and in their ability to function during their daily lives," says Vale, now an interventional cardiologist at St. Vincent's Hospital in Sydney, Australia.
After an average follow-up of 32 months, one VEGF-1 patient had received a heart transplant, five underwent angioplasty to clear clogged arteries in other parts of the heart, three had suffered nonfatal heart attacks, and one suffered a stroke.
In the second study, Schatz and his co-workers reported results from a 30-patient study of a different form of the factor, called VEGF-2, conducted at five medical centers. Participants ranged from 39 to 77 years old, and 80 percent were men. Fifty-seven percent had class IV angina before receiving the therapy, 43 percent had class III. Angina classification is related to the severity of pain. Class IV is the most severe angina.
One patient died shortly after surgery to receive the therapy. After an average follow-up of 599 days (about 1½ years), six patients had revascularization procedures, one of the remaining 29 patients had died, two had suffered nonfatal heart attacks and one had a stroke. At the end of the follow-up period, none of the patients had class IV angina, 17 percent had class III angina and 83 percent had either class I or class II angina.
"The question now is why so many of our patients - all but two - are still alive," Schatz says. "Studies have shown that 20 percent to 25 percent of people with advanced coronary artery disease and this level of angina die each year. So these results are striking. We don't know exactly why it works because we don't actually see new blood vessels on the angiograms, but when it does work, the clinical results are impressive.
"When I met one of my patients before treatment, he was at death's door," Schatz adds. "Two years after treatment he remains pain-free and he's digging ditches in his backyard and pouring concrete."
Both studies used similar procedures. A four-to-six inch incision was made in the patient's chest to expose the heart. Researchers used a syringe to inject the VEGF gene into the heart muscle.
Unlike many forms of gene therapy that use a deactivated virus to carry a gene into cells, both VEGF teams used a plasmid, a single strand of DNA that is injected into the heart muscle. The gene was injected into the blood-starved part of the heart. When heart cells lack oxygen, they develop additional receptors, or cellular "docking ports," for VEGF.
Inserting extra copies of the VEGF gene enables a cell to make more of the growth factor to stimulate new blood vessel development. A major concern about VEGF therapy has been that it might cause cancer in some patients. Cancerous tumors need blood vessels to grow into them before they can develop to a detectable size. None of the VEGF-1 patients has developed evidence of cancer that could be related to the treatment. Cancer did occur in one VEGF-1 patient, "but it was a very slow-growing tumor and not related to the gene itself," says Vale. No cancers were seen in VEGF-2 patients.
"We all agree that this novel therapy has to undergo a randomized trial to prove that we are not seeing a placebo effect," says Schatz. "The results thus far suggest that these data will hold up over time."
He said researchers hope to begin a 10-center study of VEGF gene therapy in 200 patients early next year.
Co-authors with Dr. Vale are: Douglas W. Losordo, M.D.; Charles L. Milliken, M.S.; Darryl D. Esakof, M.D; Michael Maysky, M.D.; Kishor Lathi, M.D.; and James F. Symes, M.D.
Co-authors with Dr. Schatz are: John Patrick Reilly, M.D.; Mark A. Grise, M.D.; Giacomo A. Delaria, M.D.; J. J. Tyner, M.D.; Peter R. Vale, M.D.; James F. Symes, M.D.; Gary L. Schaer, M.D.; John J. Lopez, M.D., Joseph Van Camp, M.D.; Timothy D. Henry, M.D.; Wayne Richenbacher, M.D.; and Douglas W. Losordo, M.D.
(Note: This will be included in a news conference on Tuesday)
For information Nov. 10-14, contact Carole Bullock or Maggie Francis at the Hilton Anaheim Hotel.
Abstracts 1257 & 1722
NR01 - 1366 (SS01/Vale/Schatz)