A Murine Model of Type 2N VWD Was Developed By CRISPR/Cas9 Gene Editing and Recapitulates Human Type 2N VWD

Von Willebrand Disease (VWD) is caused by either an inherited deficiency of von Willebrand factor (VWF) protein or synthesis of a dysfunctional von Willebrand factor (VWF) that is referred to as a type 2 variant. One of the important functions of VWF is to serve as a carrier protein for FVIII - prolonging FVIII's plasma half-life from <2 hrs without VWF to 10-12 hrs with VWF. A variant form of VWF was identified in 1982 in which VWF did not bind FVIII resulting in FVIII's rapid clearance and a phenotype similar to moderate hemophilia and currently referred to as type 2N VWD. Type 2N VWD is caused by an autosomal recessive variant of VWF in which mutations in the D'D3 region of VWF cause decreased or absent binding of FVIII to VWF resulting in rapid FVIII clearance similar to that seen in the absence of VWF. These individuals may have a type 2N mutation on each of their VWF alleles or, more commonly, have 1 allele with a 2N mutation and their 2nd allele contains a null mutation (producing no VWF). In each of these scenarios, only functionally abnormal VWF is synthesized, resulting in reduced or absent FVIII binding, rapid FVIII clearance, and a marked reduction in plasma FVIII. While Lillicrap and coworkers have demonstrated 2N VWF expression by hydrodynamic transfection in a VWF-/- mouse, their approach represents a model of plasma 2N VWF dysfunction but does not recapitulate human 2N VWD where the abnormal VWF is not only in plasma, but also in endothelial cells and plate...
Source: Blood - Category: Hematology Authors: Tags: 321. Blood Coagulation and Fibrinolytic Factors: Animal Models and Therapeutic Targets in Thrombosis and Hemostasis Source Type: research