Genevieve McCluskey, Marco Heestermans, Ivan Peyron, Eloise Pascal, Marie Clavel, Eric Bun, Emilie Bocquet, Christelle Reperant, Sophie Susen, Olivier D Christophe, Cecile V Denis, Peter J Lenting, Caterina Casari
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引用次数: 0
Abstract
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 factor VIII (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 of 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 ten days and normalized hemostasis in a tail-clip model in hVWD1 mice. Here, we describe the development of our unique humanized mouse model for VWD-type 1 and a promising new therapeutic that corrected hemostasis in these mice.
期刊介绍:
Haematologica is a journal that publishes articles within the broad field of hematology. It reports on novel findings in basic, clinical, and translational research.
Scope:
The scope of the journal includes reporting novel research results that:
Have a significant impact on understanding normal hematology or the development of hematological diseases.
Are likely to bring important changes to the diagnosis or treatment of hematological diseases.