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In vivo modulation of a dominant‐negative variant in mouse models of von Willebrand disease type 2A

Abstract : Background: Treatment options for patients suffering from von Willebrand disease (VWD) are limited. Willebrand factor (VWF) is a polymeric protein that undergoes regulated dimerization and subsequent multimerization during its biosynthesis. Numerous heterozygous variants within the VWF-gene display a dominant-negative effect and result in severe von Willebrand disease (VWD). Previous studies have suggested that preventing the assembly of wild-type and mutant heteropolymers using siRNAs may have beneficial effects on VWF phenotypes in vitro. Objectives: To study heterozygous dominant-negative variants in vivo, we developed a mouse model of VWD-type 2A and tested two independent strategies to modulate its detrimental effect. Methods: The p.P1127_C1948delinsR deletion/variant, causing defective VWF multimerization was expressed in mice as a model of VWD-type 2A variant. Two corrective strategies were applied. For the first time in a mouse model of VWD, we applied siRNAs selectively inhibiting translation of the mutant transcripts and we combined the VWD-type 2A deletion with the Cys to Arg substitution at position 2773, which is known to prevent dimerization. Results: The RNA silencing approach induced a modest but consistent improvement of the VWF multimer profile. However, due to incomplete efficiency, the dominant-negative effect of the original variant could not be completely prevented. In contrast, the DNA-approach resulted in increased antigen levels and restoration of a normal multimer profile. Conclusions: Our data showed that preventing the detrimental impact of dominant-negative VWF variants by independent molecular mechanisms has beneficial consequences in vivo, in mouse models of dominant VWD.
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Submitted on : Thursday, October 29, 2020 - 1:30:37 PM
Last modification on : Monday, December 13, 2021 - 9:17:31 AM
Long-term archiving on: : Saturday, January 30, 2021 - 6:20:03 PM


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Matteo Campioni, Paulette Legendre, Cécile Loubiere, Barbara Lunghi, Mirko Pinotti, et al.. In vivo modulation of a dominant‐negative variant in mouse models of von Willebrand disease type 2A. Journal of Thrombosis and Haemostasis, Wiley, 2020, Online ahead of print. ⟨10.1111/jth.15131⟩. ⟨inserm-02983110⟩



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