Potential new treatment for haemophilia developed by Cambridge researchers

Around 400,000 individuals around the world are affected by haemophilia, a genetic disorder that causes uncontrolled bleeding. Haemophilia is the result of a deficiency in proteins required for normal blood clotting – factor VIII for haemophilia A and factor IX for haemophilia B. Currently, the standard treatment is administration of the missing clotting factor. However, this requires regular intravenous injections, is not fully effective, and in about a third of patients results in the development of inhibitory antibodies. Nearly three-quarters of haemophilia sufferers have no access to treatment and have a life-expectancy of only 10 years.

In a study published online today in Blood, the Journal of the American Society of Hematology, researchers report on a novel approach that gives the clotting process more time to produce thrombin, the enzyme that forms blood clots.  They suggest this treatment could one day help all patients with haemophilia, including those who develop antibodies against standard therapy. The therapy is based on observations relating to a disorder associated with excessive clotting, known as factor V Leiden.

“We know that patients who have haemophilia and also have mutations that increase clotting, such as factor V Leiden, experience less-severe bleeding,” says study co-author Dr Trevor Baglin, Consultant Haematologist at Addenbrooke’s Hospital, Cambridge University Hospitals.

Dr Baglin and colleagues therefore pursued a strategy of reducing the activity of an anticoagulant enzyme, known as activated protein C (APC). The principal function of APC is to breakdown the complex that makes thrombin, and the factor V Leiden mutation slows this process. The team, led by Professor Jim Huntington, exploited this insight by developing a specific inhibitor of APC based on a particular type of molecule known as a serpin.

“We hypothesized that if we targeted the protein C pathway we could prolong thrombin production and thereby induce clotting in people with clotting defects, such as haemophilia sufferers,” says Professor Huntington, from the Cambridge Institute for Medical Research at the University of Cambridge. “So, we engineered a serpin that could selectively prevent APC from shutting down thrombin production before the formation of a stable clot.”

To test their theory, the team administered the serpin to mice with haemophilia B and clipped their tails. The researchers found that the amount of blood loss decreased as the dose increased, with the highest dose reducing bleeding to the level found in normal mice. Further studies confirmed that the serpin helped haemophilia mice form stable clots, with higher doses resulting in faster clot formation. The serpin was also able to increase thrombin production and accelerate clot formation when added to blood samples from haemophilia A patients.

“It’s our understanding that because we are targeting a general anti-clotting process, our serpin could effectively treat patients with either haemophilia A or B, including those who develop resistance to more traditional therapy,” adds Professor Huntington. “Additionally, we have focused on engineering the serpin to be long-acting and to be delivered by injection under the skin instead of directly into veins. This will free patients from the inconvenience of having to receive infusions three times a week, as is the case with current treatments.”

The research team hopes that the discovery can be rapidly developed into an approved medicine to provide improved care to haemophilia sufferers around the world.

“Within three years, we hope to be conducting our first-in-man trials of a subcutaneously-administered form of our serpin,” says Dr Baglin. “It is important to remember that the majority of people in the world with haemophilia have no access to therapy. A stable, easily-administered, long-acting, effective drug could bring treatment to a great deal many more haemophilia sufferers.”

This study forms part of a patent application, filed in the name of Cambridge Enterprise, and the modified serpin is being developed by a start-up company, ApcinteX, with funding from Medicxi.

Adapted from a press release by American Society of Hematology.

Reference
Polderdijk, SGI et al. Design and characterization of an APC-specific serpin for the treatment of haemophilia. Blood; 27 Oct 2016;