Gene Therapy Advances in Cardiology

The first of the new techniques, called therapeutic angiogenesis, aims to stimulate the growth of new blood vessels to perform the functions being neglected by clogged arteries. Having identified the gene for the growth factor that stimulates new blood vessel growth (angiogenesis), the researchers injected it into the legs of patients with blocked arteries in the lower extremities. Unlike other gene therapy methods that attach a missing gene to a virus or other "Trojan horse" to transport the DNA to the target cell, the current approach involves injecting  "naked" DNA directly into the patient. .

Eight of the 10 legs treated in the study showed improved blood flow and evidence of newly visible vessels following the treatment. The finding is all the more significant because all of the patients had advanced disease. About half of the patients reported improvement in walking ability and reduction in pain. The blood pressure in the treated legs also showed improvement, as measured by a ratio of arm pressure to ankle pressure.

"At the beginning of the study, the patients' ankle blood pressure was about one-third of the arm's pressure.  The 14-point increase fulfills criteria ordinarily used to indicate success after surgery or angioplasty. To my knowledge, this kind of improvement has never been shown to occur without surgery or angioplasty in this group of patients.  This kind of improvement does not occur spontaneously," reported Jeffrey Isner M.D., whose team presented the research, conducted at St. Elizabeth's Medical Center in Boston.

The growth factor produced by the gene therapy was originally identified in human tumor cells.  "To grow, tumors need a blood supply," explains Isner, "so tumor cells secrete vascular endothelial growth factor to generate new blood vessels.  The factor also is produced in the developing embryo."

Following the success in leg arteries, the researchers plan to try the therapy on the vessels of the heart. The researchers believe that the vessels are similar enough that the gene therapy should do at least as well in the heart as in the legs. Obstructed blood vessels in the heart are a leading cause of heart attack. Current approaches to treatment include the use of either clot-buster drugs such as TPA (tissue plasminogen activator) or angioplasty, a procedure that physically widens the vessels with a balloon. or other device.

"This is opening a door to genetic therapy in cardiovascular disease," said Dr. Valentin Fuster of Mount Sinai Medical Center in New York City, incoming president of the heart association.

Preventing Reblockage

The innovative gene therapy approach is designed to reduce the growth of new cells lining the grafted vein. This growth, a condition called neointimal hyperplasia, renders the vessel especially susceptible to the formation of atherosclerotic plaque, the waxy substance that can form in the arteries and block blood flow and trigger a heart attack. The technique involves bathing the vein, before it is grafted, in a solution that contains an   oligodeoxynucleotide (ODN). The ODN is a  transcription factor decoy that blocks the activity of genes necessary for neointimal hyperplasia by inhibiting the function of a protein inside the nuclei of cells.

The initial clinical study involved treatment of four patients who underwent bypass surgery to circumvent blocked leg vessels. The grafted leg vessels have remained unobstructed in the nine months since they were genetically treated, reported Michael Mann, M.D., instructor in medicine at Harvard Medical School.

The genetic treatment essentially helps the vein grafts to behave more like the arteries they replace. Veins are normally exposed to relatively low pressure from circulating blood. When used as a bypass graft, the vein is asked to function as an artery, carrying blood from the heart. The higher blood pressure exposes the graft to more stress, making it vulnerable to neointimal hyperplasia, Mann explains.

"Essentially, we're trying to manipulate the biology of the vein graft and make it behave more like an artery," says Mann. "Even though we are evaluating the technique in peripheral bypass procedures, the approach is conceptually the same for coronary bypass. Experiments have also shown that when neointimal hyperplasia is genetically inhibited, vein grafts increase their  normal muscle content and appear more like arteries. In addition they resist the rapid development of atherosclerosis usually seen in vein grafts."

A larger study is now underway comparing the new gene therapy method with conventional bypass surgery.