Heparin enzyme


O pen-heart surgery, which is performed more than 590,000 times

annually in the United States, would not be possible without heparin. Lacking this drug, blood could clot in the tubing of the machines used during these procedures—and that could put the patient’s life at risk.

But doctors have to reverse heparin’s action after such procedures, so that a person’s blood can rapidly regain its ability to clot and thereby heal breaks in internal tissue and in the skin.

Thus to prevent complications from bleeding after open-heart surgery—or some-times following other procedures—physicians today finish by administering a second drug, protamine, which binds to heparin, rendering it useless.

But because the administration of heparin during surgery is not an exact science, gauging how much heparin remains in the person afterwards and therefore how much protamine to give can be difficult. Moreover, protamlne sometimes leads to adverse reactions such as lowered blood pressure, difficult breathing, and a slow heart beat, or does not work as well as expected.

Some 20 years ago, while studying enzymes—compounds that break up proteins and other substances—for his doctoral thesis at MIT, Robert S. Langer Jr. became intrigued with the problems surrounding the medical use of heparin. He conceived of a possible alternate therapy using heparinase, the enzyme that chops up heparin molecules. Now a professor of chemical and biomedical engineering, over the years Langer has gone on—with Charles L. Cooney, a professor of chemical engineering at the school—to found a virtual institute of heparinase research.

They and their team members have developed ways to produce and purify forms of the compound from the best studied species—a soil bacteriurn—that naturally makes the enzyme. They have isolated the gene needed to make the enzyme by genetic engineering. They have safely deactivated hcparin in lab animals by injecting hcparinase into the bloodstream. And with results suggesting more research avenues, the engineers have spun off into work exploring whether heparinase could help halt rapid blood-vessel growth (a process critical in diseases such as certain forms of cancer), and developing a device that might be useful not only for administering heparinase hut also for reducing the amount of the “bad” form of cholesterol found in the blood.

Among the companies interested in the work is IBEX Technologies of Montreal. IBEX finished its first human trial of injected heparinase this past summer, with the 24 healthy people who received the enzyme tolerating it well, says Robert Heft, president and chief operating officer of the company. The company began a second human trial in late August, 1994, giving first heparin and then heparinase to volunteers. Other trials will follow; if all goes well as hoped for the research phase required by the U. S. Food and Drug Administration. Heft notes, his company could receive approval to market heparinase by the end of 1998.


Meanwhile, the MIT researchers have expanded their focus to developing a differ-ent way to deliver heparinasc to heparm molecules. During the course of animal studies in the I 980s the Langer-Coonev team found that heparinase can trigger allergic reactions if injected more than once or twice in the same patient— a situation that could sometimes crop up. The researchers have therefore created a device that both keeps heparinase outside the body—so the compound does not meet up with critical parts of the immune system that would mount a response— and mixes the enzyme with heparin. The group has designed an instrument that could be installed in the machine tubing through which blood returns to a patient during, say, heart surgery. (The exposure to heparinasc by only quickly flowing blood can’t trigger an allergic reaction.)

The mixing device houses a filter made of synthetic heads, hollow cellulose fibers or other materials that bind the heparinase so it can’t enter the body—while still being able to react chemically with heparin. During initial design tests on animals s the researchers have found that the unit works as expected. They are now tweaking the instrument to be efficient, sturdy, and practical enough for clinical use, although Langer is uncertain about when it will actually be ready. The device could also have other applications. By substituting other enzymes for hepaninase, for example, doctors might someday employ the instrument to reirn)ve toxins from blood Langer has studied how an enzyme immobilized by substances in the instrument can alter low-density lipoprotcins (LDLs), the harmful form of blood cholesterol that can lead to heart disease and speed their removal from the blood (So far, this enzyme can’t be safely injected into the bloodstream.) W.R. Grace & Co.’s Grace Biomedical Group of Lexington, Mass., which has helped sponsor Langer’s work on LDL removal, has an option to license the device, says Claudy Mullon, manager of biomedical research at Grace and a former postdoctoral fellow in Langer’s lab.

MIT researchers are also trying to improve the stability and effectiveness of heparinase and increase its production levels. Ram Sasisekharan, a medical scient-ist, is overseeing a group that over the past six years has been using polymerase chain reaction technology, which greatly multiplies particular genes so they can he separated from a battery of other genes in solution, to come up with more than two dozen mutant forms of the enzyme with slightly varying attributes Sasisekharan is also working on producing larger hatches of heparinase by sealing up the apparatus used to make the compound.

Improved production levels of heparinase could also he critical if another research avenue someday proves to have therapeutic value. During the course of its work, the MIT team has found that heparin occurs naturally around the out-side of tissue cells, where it can hind to certain chemical products critical to cell growth, facilitating new blood-vessel formation. This process becomes very active during the course of about 20 diseases, including the development of solid tumors such as those found in many cancers. In 1994 the researchers published findings that heparinase dramatically inhibits new blood-vessel formation. Over the next several years, the group will investigate whether heparinase can halt blood-vessel formation in the eyes of animals, for potential use as a treatment for retinopathy, an eye condition that can cause blindness. An important part of that effort will be studies on ways to efficiently deliver the enzyme to the sites of blood-vessel formation.




November/December 1995. (Pgs. 12-13)

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