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University of Rochester Team Makes Progress on Advanced FVIII
 

Decades of study by a team of researchers at the University of Rochester Medical Center in New York into the makeup of factor VIII (FVIII) have produced results that might improve the clotting ability of FVIII in hemophilia A patients. The lead investigator of the team’s most recent breakthrough is Philip Fay, PhD, professor in the Department of Biochemistry and Biophysics.

Fay, partnering with Hironao Wakabayashi, MD, PhD, research assistant professor of biochemistry and biophysics at the medical center, targeted three amino acids—Asp519, Glu665 and Glu1984--because they had the potential, if replaced, to improve the overall stability of the FVIII protein. Maintaining the protein’s stability, which is an issue during factor manufacturing or upon initial exposure to a patient, could greatly enhance its effectiveness. Another advantage to this approach is that the technique changes a component within the protein, keeping it “buried.” By remaining hidden from the patient’s immune system, the enhanced FVIII can then perform its clotting function while eluding an inhibitor response by the body.

Fay said that the goal of the research is to “improve upon nature” by developing better functioning FVIII proteins than those found in the nonhemophilic population. He also noted that this type of FVIII would be particularly well suited to treat hemophilia patients. “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,” Fay said. “In patients with hemophilia, however, enhanced clotting is desirable. On the other hand, we have sought to change the protein’s structure as little as possible, because the immune system is more likely to react the more we change it.”

This most recent discovery follows a 2005 study in which Fay and Wakabayashi demonstrated that by exchanging one amino acid for another (glutamic acid with alanine) at a specific location on FVIII they could achieve a two-fold increase in its ability to bind with factor IX. The binding of factors VIII and IX are important steps in the so-called “clotting cascade.”

Fay and Wakabayashi have already filed patent applications for the redesigned FVIII. “Our goal from these redesigns remains to prolong the treatment effect, make it less expensive and lessen the chances of rejection by the immune system,” Fay said.

The study, “Combining mutations of charged residues at the A2 domain interface enhances factor VIII stability over single point mutations,” was published in the December 2008 issue of the Journal of Thrombosis and Haemostasis.

Source: Science Daily, December 28, 2008

 

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