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Now in vivo: altering endothelial cells.

Now in vivo: Altering endothelial cells

Like the bed of a swiftly moving river, endothelial cells lining blood vessel walls maintain intimate contact with blood flowing throughout the body. Such proximity tantalizes researchers who seek cells they might genetically alter to deliver a steady flow of medication through the bloodstream or secrete chemicals to bust blood clots.

Investigators have already succeeded in inserting some types of genes into the DNA of cultured endothelial cells, causing the cells to secrete the gene's enzyme product in vitro. Now, for the first time, two independent research groups report successfully implanting genetically altered endothelial cells into the arteries of live animals. The cells, they say, produced the desired enzyme product.

The researchers chose an enzyme that is easily detectable but cannot treat disease. Nevertheless, they say their work takes a key step toward genetic therapy via the circulatory system. Moreover, suggests James M. Wilson of the University of Michigan Medical Center in Ann Arbor, some of their findings may lead to improved success with small-diameter vascular grafts -- often required by diabetics who have damage to small blood vessels.

Wilson and his colleagues at Tufts University School of Medicine in Boston and The Whitehead Institute for Biomedical Research in Cambridge, Mass., used a retrovirus to insert a bacterial gene called lacZ into endothelial cells extracted from the blood vessels of seven dogs. They grew the genetically altered cells along the interior of Dacron tubes 4 millimeters in diameter, forming grafts to splice into the carotid arteries of the same dogs. Five weeks later, the researchers stained the cells to reveal betagalactosidase, an enzyme produced by the lacZ gene. They describe their work in the June 16 SCIENCE.

According to W. French Anderson of the National Heart, Lung, and Blood Institute, physicians perform about 350,000 vascular grafts in the United States each year and about 100,000 of these fail, in part because small-diameter grafts tend to clog or collapse. If researchers could alter the endothelial cells in these grafts to produce vessel-dilating chemicals, the success rate might dramatically improve, Anderson suggests.

Wilson says one goal of his research is to lay the foundation for clinical trials of a genetically engineered graft. "We thought a lot about clinical applications in the design of our experiment," he says. But developing a drug-delivery system from endothelial cells may prove difficult even if the basic genetic manipulation is achieved, he adds. "You would need a lot of cells to make a lot of protein .... A [vessel-like] graft may not have enough surface cells; a radiator-like device to increase the surface area may be needed."

In a separate experiment described in the same issue of SCIENCE, Elizabeth G. Nabel and her colleagues at the University of Michigan Medical Center infused lacZ-containing endothelial cells into the leg arteries of nine pigs. Upon removing portions of the arteries two to four weeks after seeding them with the genetically altered cells, Nabel found evidence that the cells were producing the lacZ enzyme. She terms her nonsurgical technique "complementary" to that of Wilson and his colleagues. "It can be useful to work directly with an artery through the use of a catheter instead of requiring surgery," Nabel notes.

Both Wilson and Nabel say they have begun experiments to determine whether endothelial cells can produce the enzyme for more than a few weeks. And Wilson told SCIENCE NEWS he has recently engineered endothelial cells to produce two other major protein classes--membrane and secreting proteins--in addition to enzymes. Anderson says he and others have begun work on genetically engineering endothelial cells to produce tissue plasminogen activator, a compound that destroys blood clots.
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Author:Cowen, R.
Publication:Science News
Date:Jun 17, 1989
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