Borgess RI Involved In Landmark Study
KALAMAZOO — Cardiologists at Borgess Research Institute are participating in what's being touted as a "landmark" cardiovascular study that's evaluating a new gene therapy's effectiveness in growing new blood vessels in diseased human hearts.
The new therapy is being tested for its ability to restore blood flow to oxygen-starved areas of the heart in patients with advanced coronary artery disease in order to provide some relief from the severe chest pain, or angina, that accompanies the disease.
Research scientists involved in the gene therapy trial, known as Genetic Angiogenic Stimulation Investigational Study (GENASIS), hold out hope that it will lead to a new method of treating moderate to severe angina.
According to the American Heart Association, cardiovascular diseases claimed 927,448 lives in 2002 and accounted for 38 percent of all deaths — or 1 of every 2.6 deaths in the United States.
About 6.4 million Americans have angina pectoris and an estimated 150,000 to 200,000 of them are no longer candidates for surgery or other treatments, said Tim Fischell, M.D., principal investigator on the Borgess Research Institute study and a cardiologist with Borgess Hospital's Heart Center for Excellence.
Traditional therapies for heart disease are introduced to the body by pills or injections that release drugs into the circulatory system and disperse them through the body. But in gene transfer therapy, genetic material — DNA — is directly injected into body tissue and is absorbed by the cells surrounding the tissue.
The GENASIS procedure involves injecting plasmid DNA through a catheter directly into six areas of the heart. The whole procedure takes about 40 minutes, Fischell said. Corautus Genetics Inc. of Atlanta developed the gene therapy product, which is a plasmid DNA form of Vascular Endothelial Growth Factor, or VEGF-2.
Plasmid is a unit of DNA that replicates within a cell independently of the chromosomal DNA and is used in recombinant DNA research to transfer genes between cells.
"This plasmid DNA is basically a functionally naked DNA that is put in a form that can be absorbed into the heart muscle cells," Fischell said.
As he explained it, when the plasmid DNA gets into the heart muscle cells, the gene instructs the cells to make protein, and the protein is what stimulates blood vessel growth.
In pilot studies and safety trials a few years ago, the gene transfer agent was shown to cause blood vessels to grow and increase blood flow — and therefore oxygen — to the heart, Fischell said.
In those earlier trials, 70 percent of patients reported a reduction in angina and many also experienced a "significant" reduction in episodes of angina, down from an average of 32 per week to seven per week, according to study results. The effects were purportedly sustained for at least two years.
The late Jeffrey M. Isner, M.D., a Boston-based cardiologist and one of the nation's leading authorities on gene replacement therapy, was the first to conduct studies using this particular gene transfer agent. As early as 1994, Isner's team performed the first cardiovascular arterial gene transfer and showed that blood vessels could be grown in human legs. In 1998 he began using gene therapy in human hearts.
"Based on the pilot data that has been presented and some of the data from Jeff Isner's early work, I think it's more likely than not that this will have a beneficial effect for patients," Fischell said.
"We're the only site in Michigan that is offering this treatment right now. We're trying to get word out through the media, through letters to doctors who see these patients, that we are accepting patients for the study."
More than 420 patients with moderate to severe angina will be taking part in the national study. So far, about 145 patients are enrolled nationwide, Fischell said. Cardiologists will administer three different doses — low, medium and high — to three 100-patient groups in the study, and another 100 patients will get a placebo.
GENASIS is essentially a Phase IIb study, he said. It's partially to determine what dosage works best and is the safest.
"This is the first major, randomized, clinical trial using this agent in the heart muscle," Fischell said. "We were involved in a laser trial where we were burning laser holes into the heart muscle to try to stimulate blood vessel growth, which was not very effective. But this particular agent looks like it could be much more effective."
Borgess Research Institute launched its portion of the GENASIS project several months ago and started enrolling patients for the study three weeks ago. As of last week, two patients were enrolled and two more scheduled for enrollment. Fischell said he'd like to have at least 20 participating patients and expects it will take until March to complete the trial.
When the study is done, data from all 32 study sites will go to a central data collection, processing and analyzing center to "unblind" the data and put together the results.
Fischell anticipates the results will be publicly available about a year from now. It takes a lot of time and money to do the studies and get a drug FDA approved, he said.
"It's conceivable — if the results are staggering, if the results are remarkable — that this drug could be FDA-approved after this randomized trial, but it's unlikely that the results will be that dramatic."
Most likely, a much larger, Phase III clinical trial will follow to further test the treatment dosage that has been deemed most effective.
Corautus Genetics and Boston Scientific Corp. are the corporate sponsors of the study and intend to commercialize the product at some point.