Contacts:
Gary Nelsestuen, Ph.D.,
Biochemistry Department,
(612) 624-3622
Nigel Key, M.D.,
Department of Medicine,
(612) 624-0123
Deane Morrison,
University News Service,
(612) 624-2346,
[email protected]
Embargoed by Proceedings of the National Academy of Sciences until 5 p.m. EDT Monday, April 13. Audio will be up at that time on the University of Minnesota Newsline, (612) 625-6666.
U OF Minnesota Research Points to Better Blood Clotting Control
Most of us take blood clotting for granted. A little rip, a little cut--no problem. That's because most of us have all the necessary clotting factors--the proteins that interact to produce clots. Hemophiliacs, however, lack a clotting factor and so depend on injections of the missing factor. Those injections sometimes cause too much clotting, and they're extremely expensive. But if clotting factors could be made to work better, they could be given less frequently and in smaller, less expensive doses.
That scenario has come a step closer, thanks to Gary Nelsestuen, a biochemistry professor at the University of Minnesota. Nelsestuen, along with biochemistry graduate students, has designed a new version of a crucial clotting factor and found that, in the test tube, it induced clotting much faster than the version normally made by the body. His work could lead to more efficient and cheaper treatments for hemophilia. Related technology in other proteins may someday help treat the opposite condition--excess coagulation--in other types of patients, he said. The work will be published in the April 14 issue of Proceedings of the National Academy of Sciences. Nelsestuen has applied for a patent on the process.
"I think Gary's development is great," said hemophilia researcher Nigel Key, an assistant professor of medicine at the university. "I think any new therapy for [severe cases] of hemophilia will be very welcome."
Nelsestuen studies vitamin K-dependent proteins, a class of proteins that must attach to membranes to do their jobs. Vitamin K is responsible for creating a special site on the proteins that serves to anchor the proteins to membranes. Several clotting factors fall into this class; they attach to membranes that get torn during tissue injury. Nelsestuen reasoned that if the part of the clotting factors that anchors them to a membrane worked better, then the factors as a whole would work better, too. The key to making a better protein was learning how vitamin K generates membrane-attachment sites on the proteins. Recent findings in his lab have shed light on this process and allowed the new technology.
Working with factor 7, a clotting factor used to treat the most severe cases of hemophilia, Nelsestuen found that making two simple modifications in its structure could improve its function between 4- and 100-fold. Researchers in Seattle were enlisted to help produce the modified factor 7. The next step is to see if it will work better than natural factor 7 in animal models and humans, he said.
Clotting is a complex cascade involving multiple factors, Nelsestuen explained. For hemophiliacs, the crucial part of the cascade concerns factors 7 through 10. In hemophilia A, factor 8 is missing; however, injections of factor 8 can treat the condition. Similarly, people with hemophilia B lack factor 9 and can be treated with it. But if those factors were never produced by the body, the immune system may learn to regard them as "foreign" and destroy them when they're injected. (Some hemophiliacs produce tiny amounts of the "missing" factors, and thus face no danger from their immune systems when those factors are injected.)
Luckily, large doses of factor 7 can substitute for a lack of either factor 8 or factor 9. And, because all hemophiliacs naturally produce factor 7, the immune system leaves it alone. Therefore, factor 7 is given to hemophiliacs whose immune systems reject the factor that would ideally be given.
Measuring clotting speed in several different plasma systems, Nelsestuen achieved his 4- to 100-fold speedup when he used a synthetic version of factor 7 in which two amino acids had been replaced by two other amino acids. He said the same sort of modification could also produce a more efficient factor 9, which is also a vitamin K-dependent protein. And the technique isn't just for clotting factors; it could also be extended to proteins that prevent clotting. Nelsestuen and his colleagues have already used amino acid-switching to produce a more efficient bovine anti-clotting protein and see no reason it could not work in its human counterpart. That protein, known as protein C, may be useful in preventing unwanted coagulation in several types of patients.
"There are at least six vitamin K-dependent proteins involved in coagulation, and this technique can probably improve all of them," Nelsestuen said.
Currently use of factor 7 as a bypass is limited by its great expense and lack of Food and Drug Administration approval, Nelsestuen and Key said. Key added, however, that a large clinical trial of factor 7 showed it to be effective and safer than conventional bypassing therapies. In that trial, 60 hemophiliacs from around the country, including several patients of Key, used factor 7 at home.
Key said that other bypassing therapies exist, but often cause too much clotting. Those therapies contain a mix of activated factors 7, 9 and 10, plus other clotting proteins. Key said that the most severe cases of hemophilia can easily cost $100,000 a year to treat, and that Nelsestuen's improvement should reduce that figure. He also said that similar improvements to factor 9 could allow it to be given at lower doses to hemophilia B patients.
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