Gene Therapy in Patients Grows New Arteries

Boston researchers have for the first time used gene therapy to grow new arteries in the legs of patients with severe heart disease, bypassing blocked blood vessels and restoring circulation to limbs that would otherwise have been amputated.

The unprecedented ability to grow new blood vessels could benefit not only the 100,000 heart disease patients who undergo leg bypass surgery every year, but also the 500,000 who undergo coronary artery bypasses, experts said.

The leg treatment halted both gangrene and ulcers caused by poor circulation in all but one of the 10 patients studied, eliminated pain and enabled patients to move around more freely, Dr. Jeffrey Isner of St. Elizabeth’s Medical Center in Boston told an Orlando meeting of the American Heart Assn. on Sunday.

In a second study also reported Sunday, Harvard researchers said they had successfully used gene therapy to prevent blockage in veins grafted into the legs of four heart disease patients to bypass artery blockages. About 50% of such bypasses become blocked themselves without the gene therapy, but all of the treated bypasses remained open after nine months, researchers said.

The two projects “are opening a door that is quite interesting and quite meaningful for future treatment of heart disease,” said Dr. Valentine Fuster of Mt. Sinai Hospital, president of the American Heart Assn. The two studies are “the first applying gene therapy to cardiovascular disease in humans with success,” he added.

Gene therapy involves the manipulation of a patient’s DNA to treat or cure illness. In most cases it involves replacing a defective gene with a healthy one, but in some instances, such as these, it might involve shutting a gene off or producing a therapeutic protein.

Despite the therapy’s much-vaunted prospects, proponents have had relatively few successes--in large part because they have not been able to get replacement genes into a large enough number of the patients’ cells and get them to persist long enough.

The approaches used in these two studies required only a brief period of treatment to permanently alter the course of the disease.

Isner and his colleagues studied 10 patients with severe atherosclerosis. This disease clogs arteries throughout the body, and legs are especially vulnerable because of their distance from the heart. Because of the reduced flow in their legs, the patients had severe skin ulcers, gangrene and intense resting pain that typically required heavy narcotic treatment. All other attempts at treatment had failed and the next step, without treatment, would have been amputation.

The team treated the patients with DNA that served as the blueprint for a protein called vascular endothelial growth factor or VEGF, which stimulates the growth of blood vessels. They injected the DNA into muscles at four sites along the leg at the beginning of the treatment and once again four weeks later.

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The VEGF injections stimulated new blood vessels to grow, improving the flow of blood through the legs. All of the patients had an improved ability to walk, reduced pain and improved ulcer healing. In eight of the 10 treated legs, that improved blood flow could be verified by magnetic resonance imaging. Angiograms confirmed evidence of new vessels in seven of the 10 treated limbs.

Blood pressure in the legs also improved. At the beginning of the study, blood pressure at the ankles was only one-third that in the arms. After treatment, pressure had increased to half that of the arms, a significant increase.

Only one of the patients’ legs had to be amputated--in a 39-year-old woman with severe atherosclerosis in both legs. At the start of the study, “the front half of one foot was already black due to the onset of gangrene,” Isner said, “but it had affected only the toe of the other leg.” Therapy was applied to both legs and halted the gangrene in the least affected one, but failed in the other leg “because it was too far gone,” he said.

Isner’s team is planning to enlarge the trial to include other centers and are applying to the Food and Drug Administration to conduct similar trials to circumvent coronary arteries.

Patients who are at an earlier stage of disease and still can be treated with bypasses are the focus of the second study, reported by Dr. Michael Mann of Harvard and Dr. Victor J. Dzau of Brigham and Women’s Hospital in Boston. The conventional treatment in such patients is to surgically implant a vein--usually the saphenous vein from the leg--to bypass the obstructed leg artery.

The problem is that a vein is not an artery. It is thinner and weaker because blood pressure is lower in veins. When veins are exposed to the higher pressures in the arterial system, the pressure triggers a complex set of changes called neointimal hyperplasia that leaves the veins especially susceptible to atherosclerosis, a buildup of deposits on the insides of arteries. About 30% of such grafts fail in two to five years and 50% within 10 years.

Working in animals, Mann and Dzau found a way to alter this process. Treating the tissue with a short segment of DNA, called a transcription factor decoy, inhibits the genes that trigger neointimal hyperplasia, allowing the tissue to take a different pathway in which only useful muscle tissue is produced. Once the tissue enters this pathway, moreover, the process is irreversible, Mann said, and the risk of atherosclerosis is permanently reduced.

“Basically, we’re trying to manipulate the biology of a vein and make it behave more like an artery,” Mann said.

Mann reported on the team’s studies with the first four patients they have treated. When the saphenous vein was removed from the patients’ legs, it was bathed for about 10 minutes in a solution containing the DNA for the transcription factor decoy and then implanted in the normal fashion. Nine months later, all the grafts are still unobstructed and show no evidence of neointimal hyperplasia, he said.

The team has enrolled 40 more patients in a large, double-blind clinical trial in which patients will receive either treated or untreated bypasses. The trial will eventually include 2,000 patients, he said, and should demonstrate “whether the technique will actually succeed.”

They are also planning to study the treatment in coronary artery bypasses.