Small interfering RNA–mediated allele-selective silencing of von Willebrand factor in vitro and in vivo

•Using 7C1 lipid nanoparticles, efficient endothelial delivery of siRNAs targeting VWF can be achieved.•Allele-selective silencing of VWF using siRNAs is feasible based on 1 nucleotide difference within mouse strains. [Display omitted] An imbalance in von Willebrand factor (VWF) may either lead to b...

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Published in:Blood advances 2023-10, Vol.7 (20), p.6108-6119
Main Authors: Jongejan, Yvonne K., Schrader Echeverri, Elisa, Dirven, Richard J., Paunovska, Kalina, Linthorst, Noa A., de Jong, Annika, Wellershoff, Johannes C., van der Gouw, Kim D., van Vlijmen, Bart J. M., Dahlman, James E., Eikenboom, Jeroen C. J.
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Language:English
Subjects:
Thrombosis and Hemostasis
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Summary:•Using 7C1 lipid nanoparticles, efficient endothelial delivery of siRNAs targeting VWF can be achieved.•Allele-selective silencing of VWF using siRNAs is feasible based on 1 nucleotide difference within mouse strains. [Display omitted] An imbalance in von Willebrand factor (VWF) may either lead to bleeding (von Willebrand disease, VWD) or thrombosis. Both disorders have shortcomings in the currently available treatments. VWF itself could be a potential therapeutic target because of its role in both bleeding and thrombosis. Inhibiting VWF gene expression through allele-selective silencing of VWF with small interfering RNAs (siRNAs) could be a personalized approach to specifically inhibit mutant VWF in VWD or to normalize increased VWF levels in thrombotic disorders without complete VWF knockdown. Therefore, we investigated a method to allele-selectively silence the VWF gene in mice as a therapeutic strategy. Fourteen candidate siRNAs targeting murine Vwf of either the C57BL/6J (B6) or the 129S1/SvImJ (129S) strain were tested in vitro in cells expressing B6- and 129S-Vwf for inhibitory effect and allele-selective potential. Together with a nonselective siVwf, 2 lead candidate siRNAs, siVwf.B6 and siVwf.129S, were further tested in vivo in B6 and 129S mice. Efficient endothelial siRNA delivery was achieved by siRNA encapsulation into 7C1 oligomeric lipid nanoparticles. Treatment with the nonselective siVwf resulted in dose-dependent inhibition of up to 80% of both lung messenger RNA and plasma VWF protein in both mouse strains. In contrast, the allele-selective siVwf.B6 and siVwf.129S were shown to be effective in and selective solely for their corresponding mouse strain. To conclude, we showed efficient endothelial delivery of siRNAs that are highly effective in allele-selective inhibition of Vwf in mice, which constitutes an in vivo proof of principle of allele-selective VWF silencing as a therapeutic approach.
ISSN:2473-9529
2473-9537
DOI:10.1182/bloodadvances.2023010643