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HARVARD GAZETTE ARCHIVES Gene Therapy Reduces Clogging of Arteries By William J. Cromie
A method of pressing gene fragments into transplanted blood vessels shows encouraging evidence that it can prevent clogging of life-saving heart-bypass grafts. Every year, some 600,000 pieces of vein are sewn into the hearts of hundreds of thousands of people in the United States to bypass dangerously blocked arteries. But as many as one-third of these grafts become blocked themselves. Now, researchers at Harvard-affiliated Brigham and Women’s Hospital in Boston have developed a gene-therapy technique that has prevented such closure in a small number of test patients. "We set ourselves the task of designing a bypass graft that cannot fail," says Victor Dzau, head of the research team and Hersey Professor of Theory and Practice of Physic at the Medical School. Normally, the veins are excised from the groin area then sewn into the heart. Dzau’s group added a step whereby pieces of synthetic DNA, engineered to block the inward growth of cells into blood-vessel openings, are pressed into the grafts. Inhibiting such growth has kept the arteries open. Dzau – working with Michael Mann, an instructor in medicine, and other colleagues – treated clogged leg arteries in 17 high-risk patients in this way. The researchers compared these patients with 16 others who received untreated veins. Sixty-nine percent of the patients with untreated veins suffered clogged grafts while only 29 percent of grafts in the treated group became clogged. "The results are surprisingly encouraging," notes Dzau, who is also chief of medicine at Brigham and Women’s Hospital. "The biology of leg and heart arteries is the same, so what works in one should work in the other. However, our study is too small to be definitive; we need to work with many more patients." A study of 100 patients who received the gene treatment for blocked heart arteries is under way in Germany. And "we’re in the midst of starting one that will include about 800 patients in multiple centers in this country," Dzau reveals. But Dzau doesn’t intend to sit back and wait for the outcome. He and his team have begun experimenting with "designer arteries." Made of GORE-TEX, these artificial blood vessels would hold genes engineered to release drugs that bust or prevent clotting in arteries downstream from the grafts. Another idea is to piggyback onto the designer grafts genes that release nitric oxide, a substance that relaxes blood vessels and prevents clotting. The Schwarzenegger Effect The pressure of blood flowing through arteries is higher than that coursing through thinner-walled veins. So when surgeons substitute veins for arteries, the veins quickly thicken their walls to support the added load. Such thickening is similar to developing atherosclerosis, the partial or complete blocking of blood vessels carrying vital oxygen to the heart. The culprit involves a substance called E2F, which stimulates growth of cells that line both veins and arteries. Dzau and his team designed a DNA fragment that prevents E2F from turning on genes involved with this growth. The researchers brewed a liquid containing these gene fragments and used pressure to force it into seams between the cell walls of vein grafts. Surgeons sutured these engineered veins into the legs of 17 patients. After one year, these patients were compared with 16 others who received untreated grafts at the same time and with eight who got scrambled DNA squeezed into their grafts. "We had to make sure that the effects we saw were specific for the DNA we designed to shut down clogging and not for any DNA at all," explains Dzau. "Those with treated grafts suffered no adverse effects, and transplanted veins in more than two-thirds of them remained totally unclogged." Leg grafts were used in the initial experiments because they are simpler and safer, and because the amount of opening and closing is easier to measure than in heart grafts. "The engineered grafts responded to blood flow stress like the muscles of people who lift weights and do other exercises," says Dzau. "I call it the ‘Schwarzenegger effect.’"A Blinded Study"This is the first cardiovascular gene therapy study done in a controlled, randomized, blinded fashion," Dzau says. "Randomized" means that patients were randomly assigned to one of the three groups; "blinded" refers to the fact that none of the people measuring results knew which group each patient was in. This method eliminates the possibility that other factors could account for the outcome, including diet, exercise, and psychological improvement from just being treated (placebo effect). Dzau and colleagues describe this work in detail in the Oct. 30 issue of the British medical journal Lancet. He notes that these "early findings" also offer a "promising approach" for treating atherosclerosis directly, as well as for reopening arteries that have reclogged after being opened by inflating balloons inside them (angioplasty). Creating designer arteries is a separate experiment. GORE-TEX is a material used in outdoor clothing to prevent buildup of perspiration. It contains tiny pores into which Dzau’s group squeezes so-called lining progenitor cells. Taken from a patient’s blood, these cells are cultured in laboratory dishes until they grow into specialized cells that form the blood vessels’ linings. With GORE-TEX pores providing anchorage, such cells grow and cover the surface of the graft. "We can put ‘supergenes’ into these cells which are capable of treating, even curing, what ails a person," Dzau points out. Genes that produce clot-busting proteins are one example; those that trigger the making of blood-vessel relaxants are another. Just as gene therapy done outside the body improves blood flow inside, so outdoor clothing may protect the inside of the heart.
Copyright 1999 President and Fellows of Harvard College |
