Gene therapy advances go to the heart.

By changing the genetic instructions issued within the cells that make up blood vessels in and around the heart, researchers are findings ways to replenish blood flow to damaged heart muscle. Such gene therapy also shows promise in vein grafts around a blocked vessel in the leg, an operation similar to heart bypass surgery.

These studies, though small, offer intriguing signs that such genetic manipulation may someday be an alternative to some heart surgery, researchers say.

Investigators have found it difficult to get new blood vessels to grow in areas of the heart damaged by clots that stop blood flow. Doctors usually use balloon angioplasty to open up a heart artery and a device called a stent to prop it open. Or surgeons take a vein from another part of the body and graft it onto the heart to bypass a blockage. Many patients' hearts, however, fail again when these new or repaired vessels accumulate plaque--the same kind of clogging that caused the original damage.

Using gene therapy, Jeffrey M. Isner and his colleagues at St. Elizabeth's Medical Center in Boston have treated 16 heart-disease patients who averaged two bypass operations apiece; 11 had also had one to three angioplasties. "These are patients that even cardiovascular surgeons don't like to see ... patients that come in for a second or third bypass operation--where the operation carries a higher risk," Isner says.

All the patients received DNA injections into heart muscle receiving inadequate blood supply. The DNA is a fragment of VEGF (vascular endothelial growth factor), a gene that directs blood vessel growth. Among 11 patients who have been followed for more than 90 days, Isner reports, 6 patients are entirely free of angina, a tightness in the chest that indicates restricted blood flow. Among these 11 patients, use of nitroglycerin to relieve angina has fallen from an average of 60 pills a week to 2.5.

Gene therapy is also showing some ability to limit plaque formation in grafted blood vessels in the leg. About half of all bypass grafts clog up again. At Brigham and Women's Hospital in Boston, Michael J. Mann and his colleagues bathed replacement vessels in a solution of DNA segments that suppress the growth of new cells along the inner lining of blood vessels. This gene therapy, done before surgery, improved success rates and added only 10 minutes to the procedure.

Mann reports that of 17 bypass patients treated with gene therapy, only 5 had an obstruction in the new leg vessel 7 months later. Of 16 others whose grafts weren't so treated, 10 had obstructions.

The treatment genes persist only a week or 2, but they seem to spur continuing damage control in the vessel. "A genetic switch is turned on right after surgery that [often] leads to disease," he says. "We are changing that switch."