Personalized treatment for von Willebrand disease by RNA-targeted therapies

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. Patients mainly develop mucocutaneous bleeding, like bruises, epistaxis and menorrhagia. The more severely affected patients may also develop joint bleeding, or bleeding from the gastrointestinal tract. Also, trauma, surgery or dental procedures may lead to critical bleeding events. VWD-related bleeding are caused by defects in von Willebrand factor (VWF), a large multimeric protein that is produced by endothelial cells and megakaryocytes. Most VWD patients develop the disease because of dominant-negative mutations in VWF. In this thesis we investigated whether inhibition of production of mutant VWF with limited inhibition of wildtype VWF positively affects the function of VWF and improves VWD phenotypes. We used small interfering RNAs (siRNAs) to selectively inhibit production of mutant VWF. These siRNAs were tested in several models for VWD. We indeed prove that siRNAs can distinguish a mutant and wildtype VWF allele in vitro in heterologous cell systems, ex vivo in patient-derived endothelial cells, and in vivo in a VWD mouse model. We also show in these disease models that we can improve several VWD phenotypes. These results are promising for further development of allele-specific siRNAs as a new treatment strategy for VWD.