von Willebrand disease is the most common inherited bleeding disorder. Its most prevalent form, type 1 (70–80% of cases), corresponds to a quantitative deficiency of von Willebrand factor (VWF), with reduced antigen levels, a generally normal activity-to-antigen ratio, and a normal or only slightly altered multimeric profile. This heterogeneity, combined with VWF levels that fluctuate with age, pregnancy, or exercise, complicates both diagnosis and management. Desmopressin, which promotes the release of stored VWF, remains the standard treatment, but it is ineffective in a subset of patients, difficult to manage in children, and prone to tachyphylaxis. Most importantly, therapeutic innovation has stagnated for decades, while patients' quality of life remains impaired. The development of new strategies is hampered by the lack of an adequate animal model: owing to interspecies differences, human VWF interacts poorly with murine platelets, rendering existing models of limited relevance for preclinical studies.
To overcome this obstacle, the authors generated mice selectively expressing human VWF and human glycoprotein GPIbα. This fully humanized model proved to express low levels of VWF (approximately 12%) and factor VIII (40%), with a normal multimeric profile and a preserved activity-to-antigen ratio, which led to its repositioning as a model of type 1 von Willebrand disease (hVWD1 mice). To the team's knowledge, this is the first model expressing both fully humanized VWF and GPIbα. Characterization confirmed the expected features: reduced platelet adhesion and thrombus formation in vitro, as well as a moderate and variable bleeding phenotype in vivo. This bleeding was corrected by the administration of recombinant VWF or by histamine-induced release of endothelial VWF, the latter serving as an experimental equivalent of desmopressin.
In the search for innovative treatments, the authors designed a bispecific single-domain antibody (KB-V13A12) linking VWF to albumin. The hypothesis was that VWF thus tethered to albumin would follow the FcRn receptor–mediated recycling pathway in endothelial cells, increasing circulating levels. A single subcutaneous administration was accompanied by a sustained doubling of VWF antigen levels over about ten days, an increase in multimers of all sizes, and normalization of hemostasis in a tail-transection model, with an efficacy comparable to that of recombinant VWF and histamine.
The authors acknowledge certain limitations, in particular the 129Sv genetic background that complicates breeding, the variability of in vivo assays, and the still poorly understood molecular mechanism underlying the low VWF levels. They conclude that this humanized model constitutes a unique platform for the preclinical evaluation of new therapeutic options, overcoming the incompatibility between human VWF and murine GPIbα.