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Redesigned protein accelerates blood clotting

21.07.2005


Study holds hope for next generation hemophilia treatment



Researchers have doubled the potency of a protein that drives blood to clot, according to research to be published in the July 26 edition of Biochemistry. The study results may have profound implications for the treatment of hemophilia, the inherited blood disorder that causes easy or excessive bleeding in 30,000 Americans.

In most cases, hemophilia is caused by a lack of factor VIII, one of several proteins that enable blood to solidify, or clot, to plug wounds after injury. Current preventive treatment consists of genetically engineered factor VIII administered by injection, but one quarter of those born with no factor VIII suffer severe immune reactions that render the treatment inactive. In addition, current treatment costs as much as $200,000 per patient per year. Researchers at the University of Rochester Medical Center have been studying the structure of factor VIII for 20 years, and are making subtle changes in the protein with the goal of offering more effective, less burdensome treatment.


"We set out to design a version of factor VIII that would improve on the naturally-occurring form of the protein," said Philip Fay, Ph.D., professor in the Department of Biochemistry and Biophysics at the University of Rochester Medical Center, and the study’s senior author. "A more potent form of factor VIII, one that could treat effectively with a lower dose, would reduce the cost and, potentially, avert immune reactions," Fay said.

Study Details

Blood clotting involves more than a dozen clotting factors, many named with roman numerals. They form a cascade of chemical reactions inside blood vessels following injury, with each factor, or complex of factors, activating the next in the chain. Factor VIII partners with factor IX to activate factor X, which creates a burst of thrombin, which in turn generates fibrin, the sticky protein strands that form a web-like clot over damaged tissue. Calcium, a metallic element, must be present for factor VIII to work. Factor VIII has on its surface pocket-like chains of amino acids shaped to hold calcium ions (calcium binding sites). When calcium bonds to it, factor VIII changes shape and becomes better able to bind factor IX.

In past research, Fay’s team had identified a single amino acid (out of the more than 2,300 building blocks making up factor VIII) with the potential, if replaced, to change the performance of entire protein. Researchers proved the theory in the current study by swapping out a glutamic acid naturally occurring at a specific point in a calcium binding site on factor VIII with 19 different amino acids. One of the replacements, alanine, doubled the ability of factor VIII to bind with factor IX. Results were measured by introducing each form of factor VIII into hemophilic blood plasma and recording the time it took to cause clotting.

Fay, along with Hironao Wakabayashi, M.D., a research assistant professor at the University of Rochester Medical Center and co-inventor, have filed a patent application for the factor VIII redesign used in the published study. Moving forward, Fay’s team will target additional calcium binding sites with the goal of making changes that further increase factor VIII potency.

"Our goal is to improve upon nature by developing gain-of-function factor VIII proteins that are superior to the factor VIII protein found in healthy individuals," Fay said. "These more potent forms are not likely to occur naturally since they would theoretically result in excessive clotting, blocked arteries and heart attacks in otherwise healthy people. In patients with hemophilia, however, enhanced clotting is desirable."

Greg Williams | EurekAlert!
Further information:
http://www.urmc.rochester.edu

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