A fully humanized von Willebrand disease type 1 mouse model as unique platform to investigate novel therapeutic options.

Patients suffering from von Willebrand disease (VWD) have reduced quality-of-life despite current treatment options. Moreover, innovation in VWD therapeutic strategies has essentially stalled and available treatments have remained unchanged for decades. Therefore, there is an unmet need to develop new therapeutic strategies for VWD-patients, especially for the large portion of those with VWD-type 1. Due to species differences, the available VWD murine models are not suitable for preclinical studies, making it difficult to test new therapeutic approaches in vivo. With this in mind, we generated mice selectively expressing human von Willebrand factor (VWF) and human GPIbα. Because this fully humanized model was found to express low VWF (12%) and FVIII (40%) levels with normal multimer profile and activity/antigen ratio, we repositioned it as a VWD-type 1 model (hVWD1 mice). In depth characterization of this model confirmed VWD-type 1 features with a decrease in platelet adhesion and thrombus formation in vitro. In vivo, a moderate bleeding phenotype was observed which was corrected upon the administration of recombinant-VWF or upon histamine-induced release of endothelial VWF. In search for new therapeutic options for VWD, we designed a bispecific single-domain antibody that bridges VWF to albumin (KB-V13A12). Remarkably, a single subcutaneous administration of KB-V13A12 coincided with a sustained 2-fold increase in VWF antigen levels for up to 10 days and normalized haemostasis in a tail-clip model in hVWD1 mice. We have developed a unique humanized mouse model for VWD-type 1 and a promising new therapeutic that corrected haemostasis in these mice.