A new bypassing agent mimics the pro-clotting activity of factor V Leiden and might prove effective for treating hemophilia A and B, according to preclinical research published in Blood.
“We know that patients who have severe hemophilia and also have mutations that increase clotting, such as factor V Leiden, experience less severe bleeding,” said study author Trevor Baglin, MD, of Addenbrooke’s Hospital in Cambridge, UK.
In patients with factor V Leiden, defects in the anticoagulant activated protein C (APC) mechanism lead to an overactive production of thrombin.
The researchers set out to determine if they could exploit this phenomenon to treat hemophilia by developing a direct inhibitor of APC. They modified serine protease inhibitors, known as serpins, to make them specific and efficient inhibitors of APC.
“We hypothesized that if we targeted the protein C pathway we could prolong thrombin production,” said study author James Huntington, PhD, of the University of Cambridge in the UK.
“We engineered a serpin so that it could selectively prevent APC from shutting down thrombin production before the formation of a stable clot.”
The researchers administered the serpin to mice with hemophilia B and clipped their tails. In this model, the blood loss decreased as the dose increased, with the highest dose reducing bleeding to the level of healthy mice.
Further injury models underscored that the serpin helped the majority of mice form stable clots, with higher doses resulting in quicker clot formation.
The serpin was also able to accelerate clot formation when added to blood samples from patients with hemophilia A.
“It is our understanding that because we are targeting a general anticlotting process, our serpin could effectively treat patients with either hemophilia A or B, including those who develop inhibitors to more traditional therapy,” Dr Huntington said.
“Additionally, we have focused on engineering the serpin to be both subcutaneously delivered and long-acting. This will free patients from the cumbersome thrice-weekly infusions that are necessary under many contemporary therapy regimens.”
“Within 3 years, we hope to be conducting our first-in-man trials of a subcutaneously administered form of our serpin,” Dr Baglin added.
“It is important to remember that the majority of people in the world with hemophilia have no access to therapy. A stable, subcutaneous, long-acting, effective hemostatic agent could bring treatment to a great deal many more hemophilia sufferers.”
This study forms part of a patent application by the authors, and the serpin is being developed into a therapeutic by a start-up company known as ApcinteX, with funding from Medicxi.
