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Updated: Jun 6, 2025
Production of Humanized Mouse via Thymic Renal Capsule Grafting, CD34+ Cells Injection, and Cytokine Delivery
Published on: September 27, 2021
A fully humanized von Willebrand disease type 1 mouse model as unique platform to investigate novel therapeutic
Genevieve McCluskey1, Marco Heestermans1, Ivan Peyron1
1Universite Paris-Saclay, INSERM, Hemostase inflammation thrombose HITh U1176, 94276, Le Kremlin-Bicetre.
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.
Insights
A new humanized mouse model for von Willebrand disease type 1 (VWD1) was developed. A novel bispecific antibody therapy (KB-V13A12) effectively corrected bleeding in these mice, offering hope for improved VWD treatments.
Area of Science:
- Hematology
- Translational Medicine
- Genetics
Background:
- Von Willebrand disease (VWD) significantly impacts patient quality of life, with limited therapeutic innovation.
- Current VWD treatments are insufficient, highlighting an unmet need for novel therapeutic strategies, particularly for VWD type 1.
- Existing murine models are unsuitable for preclinical VWD research due to species differences.
Purpose of the Study:
- To develop a humanized mouse model for VWD type 1 to facilitate preclinical testing.
- To identify and evaluate novel therapeutic strategies for VWD type 1.
Main Methods:
- Generation of mice expressing human von Willebrand factor (VWF) and GPIbα, characterized as a VWD type 1 model (hVWD1).
- In vitro and in vivo assessment of hemostasis in hVWD1 mice, including platelet adhesion and bleeding phenotype.
- Design and testing of a bispecific single-domain antibody (KB-V13A12) for VWF enhancement.
Main Results:
- The hVWD1 mouse model exhibited VWD type 1 characteristics, including reduced VWF levels, impaired platelet adhesion, and a moderate bleeding phenotype.
- Administration of recombinant-VWF or histamine corrected the bleeding phenotype in hVWD1 mice.
- A single dose of KB-V13A12 sustained a 2-fold increase in VWF antigen levels for ten days and normalized hemostasis in hVWD1 mice.
Conclusions:
- The developed humanized mouse model accurately recapitulates VWD type 1.
- The bispecific antibody KB-V13A12 demonstrates significant therapeutic potential for VWD type 1 by normalizing hemostasis.
