Preclinical study points to new way to treat VWD type 1

Researchers created an experimental treatment for von Willebrand disease (VWD) type 1 that aims to stabilize the protein whose defect causes the disease, increasing its activity to help normalize blood clotting.

The team described the development and preclinical proof of concept for their new treatment in the study, “A bispecific nanobody for the treatment of von Willebrand disease type 1,” published in Blood. 

VWD is caused by a lack of functional von Willebrand factor (VWF), a protein that helps blood clot. Reduced VWF protein activity means blood cannot clot properly, which leads to disease symptoms. In VWD type 1, which is the most common form of the disease, VWF protein levels are lower than normal, but the protein is still present in small amounts.

The team of scientists in France set out to test the idea that it might be possible to treat VWD type 1 by increasing the stability of the existing VWF protein. The scientists reasoned that, if the protein were more stable, it would last longer in the body and be better able to control bleeding.

“Given that VWF is fully functional in VWD type 1 patients and is only restricted by its concentration, we hypothesized that increasing endogenous VWF levels by prolonging its half-life could be a potential option,” the scientists wrote. Half-life refers to the time it takes for the concentration of a substance to decrease to half of its initial amount in the body; a longer half-life essentially means the protein is more stable and remains active for longer in the body.

Higher protein levels, reduced bleeding

The scientists created a novel therapy consisting of two fused nanobodies, which are tiny antibody fragments. One of the nanobodies was designed to bind to the VWF protein, while the other binds to albumin, a blood protein that is normally very stable because it’s able to interact with other proteins that stop it from being broken down. The researchers noted that fusing therapies to albumin is a common strategy used to make medicines more stable and last longer in the body.

The scientists dubbed their nanobody therapy KB-V13A12. In proof-of-concept experiments done in a mouse model of VWD type 1, the researchers found that treatment with KB-V13A12 could increase VWF protein levels by twofold.

“Furthermore, the higher the dose, the longer VWF remained increased at these levels,” the researchers wrote, noting that at the two highest tested doses, VWF levels were above initial levels after 14 days.

The higher VWF protein levels were accompanied by significantly reduced bleeding in a standard assessment.

“The increased VWF levels obtained after a single subcutaneous [under-the-skin] injection are associated with an increased hemostatic [blood clotting] potential, thereby correcting the bleeding tendency in [VWD type 1] mice,” the researchers wrote.

The scientists said their therapy “could be considered as a potential candidate for a prophylactic treatment option for patients with VWD type 1,” though they noted a need for further studies before the new treatment can start being tested in humans.