Reduce Bleeding, Complications : Genetically Engineered Clot Dissolvers Promising
Scientists are using genetic engineering techniques to develop new drugs designed to save heart attack victims by zeroing in on and dissolving clots that have cut off blood flow to their hearts.
Experimental versions tried in the test tube appear to be more effective than existing clot dissolving substances and, because they are tailored specifically to attack the clot, may not cause excessive bleeding and other complications.
“We’re tremendously encouraged,” said Dr. Edgar Haber, chief of cardiology at the Massachusetts General Hospital who is heading the research. “It’s very exciting.”
According to the American Heart Assn., about 1.5 million Americans have heart attacks each year and about 540,000 die, making heart attacks the nation’s leading cause of death.
Triggered by Clots
Most heart attacks are triggered when blood clots clog arteries leading to the heart that have become narrowed by fatty buildups and cut off blood flow to the heart.
Substances that dissolve the clots restore blood flow to the heart, limiting damage to heart muscle and increasing the chances that heart attack victims will survive.
For years, doctors have been using a variety of naturally occurring enzymes to treat heart attack victims. The enzymes work primarily by acting on a protein known as fibrin, which forms the major structure of clots.
But because the agents also attack a substance known as fibrinogen in the blood, which is needed to form fibrin, the enzymes tend to cause excessive bleeding in patients.
In work published in September in the Journal of Biological Chemistry, Haber and his colleagues chemically combined the clot-dissolving enzyme urokinase with an antibody that specifically attacks fibrin.
More Powerful Combination
Experiments in a test tube found that the combination was 250 times more powerful than urokinase alone.
In another study to be published in the November issue of the Proceedings of the National Academy of Sciences, the researchers combined the same antibody with another enzyme known as tissue plasminogen activator (tPA).
When that combination was tested on a rabbit with a clot in a vein, it was found to be several times more potent than tPA alone. More importantly, tests showed that the combination appeared to have little effect on the overall amount of fibrinogen in the rabbit’s blood.
In a third study published in the Oct. 1 issue of the Proceedings of the National Academy of Sciences, the researchers used genetic engineering methods to produce a new variation of the tPA-antibody combination.
The researchers removed portions of the genes that produce the antibody and tPA and inserted the altered genes into a cell, which then produced a new version of the molecule.
The changes were aimed at removing characteristics of the molecule that trigger an immune response by the patient. Currently, tPA can usually only be used once. The first use triggers an immune response that causes an allergic reaction that neutralizes the molecule when it is used again.
Experiments in a test tube found that the new molecule retained its ability to specifically attack only fibrin as well as 70% of its clot-dissolving power, Haber said.
