Allele-selective von Willebrand factor silencing

Area of Science:

• Hemostasis and Thrombosis Research
• Molecular Medicine
• Genetic Therapies

Background:

• Von Willebrand Factor (VWF) is critical in hemostasis, with deficiencies causing von Willebrand disease (VWD) and high levels linked to thrombotic risk.
• Current treatments for VWD and thrombotic disorders have limitations, necessitating novel therapeutic strategies.

Purpose of the Study:

• To review the concept, applications, and feasibility of allele-selective VWF inhibition.
• To discuss the potential of VWF silencing as a therapeutic approach for VWD and thrombotic disorders.

Main Methods:

• Utilizing small interfering RNAs (siRNAs) to selectively silence one VWF allele based on single nucleotide differences.
• Evaluating the efficacy of allele-selective VWF silencing in vitro and in vivo models.

Main Results:

• Successful phenotypic improvement in VWD models through allele-selective VWF silencing.
• Demonstrated reduction in thrombosis development in preliminary studies without increased bleeding risk.
• VWF silencing normalizes VWF multimer composition and increases functional VWF levels in VWD.

Conclusions:

• Allele-selective VWF silencing is a feasible and effective strategy for treating VWD by normalizing VWF levels and composition.
• This approach shows potential for reducing thrombotic risk by lowering VWF levels without inducing a bleeding phenotype.
• The review also summarizes other novel VWD treatments presented at the 2025 ISTH Congress.