Gene Therapy To Treat Angina Appears Safe

The Angiogenic GENe Therapy (AGENT) trial is the first placebo-controlled, double-blind trial of the therapy in humans and tested the safety and effectiveness of injecting a growth factor gene into the heart. Researchers found unexpected but significant improvements in exercise times for the sickest group of patients who received the gene therapy.

“There is no product approved to stimulate the growth of new blood vessels,” says Cindy Grines, M.D., lead author of the study and director of the cardiac catheterization laboratories and the interventional cardiology training program at William Beaumont Hospital in Royal Oak, Mich. “We think the growth factor gene used here restarts this natural response. This is a completely new and different approach.”

Angina is a major cause of disability worldwide and affects an estimated 7 million people in the United States. The condition, marked by chest pain, occurs when blood vessels cannot get enough oxygen-rich blood to the heart to meet the increased demand during physical exertion. The body’s first response to reduced blood flow to the heart, called ischemia, is to grow tiny new “collateral” blood vessels to help blood flow around the blockage – a process called angiogenesis. For unknown reasons, the process eventually switches off.

Previous studies that injected angiogenic proteins (the products of genes that activates angiogenesis) into the heart to stimulate collateral vessel growth have been unsuccessful in the long term, possibly because the protein has a short half-life and is quickly used up, she says. Gene therapy may be a better approach than protein therapy, Grines adds, because the heart can incorporate the gene and allow continued production of the angiogenic protein for weeks. Treatment for angina currently takes two approaches. One is drugs that reduce the heart’s oxygen needs by slowing the heart rate or dilating blood vessels. The second option is to bypass the blocked vessels with surgery or open them with angioplasty, in which a balloon-tipped catheter is inserted into the vessel and inflated to widen the channel.

The researchers studied 79 men and women with coronary artery disease and mild to moderate angina. They infused an inactive virus (called Ad5) containing the human FGF4 gene, which can stimulate collateral blood vessel development, into the blood vessels supplying the hearts of 60 men and women. The virus-gene combination is called Ad5-FGF4. Another 19 subjects served as controls who got a placebo that was not expected to have any effect.

Subjects’ average age was 60, about half had experienced a previous heart attack, about one-fourth had a previous bypass surgery, and half had hypertension. In the placebo group the average duration of angina was 27 months. In the gene-treated group the average duration was 56 months.

The researchers determined that 87 percent of the gene therapy agent stayed in the heart and none of the protein product linked to the gene was detected elsewhere in the circulatory system. This indicates that the agent targets and tightly binds to heart cells.

The researchers compared each subject’s exercise treadmill time (ETT) before and after therapy or placebo. At the beginning of the study, average ETT was 9.4 minutes for the placebo group, and 9 minutes for the treatment group. Overall, patients who received the gene tended to have greater improvements in ETT than those who got the placebo. At four weeks, the treated group increased ETT by an average of 1.3 minutes compared with 0.7 minutes for placebo. Among the 50 sickest patients, those in the treatment group improved 1.6 minutes compared with 0.6 minutes in the placebo group. In many patients the improvement over baseline ETT was comparable to that seen after surgical interventions or angioplasty, says co-author Robert L. Engler, M.D., a cardiologist at the Veterans Administration San Diego Health Care System who helped develop the gene therapy. “The results of this study are very encouraging because the response that we saw was far in excess of what we would have expected. Our estimate was that we would have needed a lot more patients to detect any effect on ETT,” says Engler, who is also a professor at the University of California in San Diego.

He stresses that the small number of subjects prohibits drawing any final conclusions about the effectiveness. “Proving effectiveness will take a much larger pivotal trial, called AGENT 3, which is currently under way in 100 centers in the United States.”

Co-authors include: Matthew W. Watkins, M.D.; Greg Helmer, M.D.; William Penny, M.D.; Jeffrey Brinker, M.D.; Jonathan D. Marmur, M.D.; Andrew West, M.D.; Jeffery J. Rade, M.D.; Pran Marrott, MRCP, M.Sc.; and H. Kirk Hammond, M.D.

Financial disclosure: Drs. Engler and Hammond are founders and consultants for Collateral Therapeutics, Inc., which developed Ad5-FGF4 jointly with Berlex Laboratories, Montville, N.J. Dr. Marrott is a vice president of clinical cardiovascular research at Berlex Laboratories. None of the principal investigators who enrolled patients in the trial own stock in, or are paid by, C.T.I. or Berlex. The study received financial support from Schering A.G. and C.T.I.