{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T02:44:43Z","timestamp":1785465883474,"version":"3.56.0"},"reference-count":41,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,10,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u00a0vitro 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\u00a0vivo 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\u00a0vivo proof of principle of allele-selective VWF silencing as a therapeutic approach.<\/jats:p>","DOI":"10.1182\/bloodadvances.2023010643","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T15:51:13Z","timestamp":1689781873000},"page":"6108-6119","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":22,"title":["Small interfering RNA\u2013mediated allele-selective silencing of von Willebrand factor in\u00a0vitro and in\u00a0vivo"],"prefix":"10.1182","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1118-7005","authenticated-orcid":false,"given":"Yvonne K.","family":"Jongejan","sequence":"first","affiliation":[{"name":"1Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4094-2054","authenticated-orcid":false,"given":"Elisa","family":"Schrader Echeverri","sequence":"additional","affiliation":[{"name":"2Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9626-9925","authenticated-orcid":false,"given":"Richard J.","family":"Dirven","sequence":"additional","affiliation":[{"name":"1Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4894-5751","authenticated-orcid":false,"given":"Kalina","family":"Paunovska","sequence":"additional","affiliation":[{"name":"2Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8819-3446","authenticated-orcid":false,"given":"Noa A.","family":"Linthorst","sequence":"additional","affiliation":[{"name":"1Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6124-535X","authenticated-orcid":false,"given":"Annika","family":"de Jong","sequence":"additional","affiliation":[{"name":"1Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes C.","family":"Wellershoff","sequence":"additional","affiliation":[{"name":"1Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim D.","family":"van der Gouw","sequence":"additional","affiliation":[{"name":"1Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-6453","authenticated-orcid":false,"given":"Bart J. M.","family":"van Vlijmen","sequence":"additional","affiliation":[{"name":"1Division of Thrombosis and Hemostasis, Department of Internal Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7580-436X","authenticated-orcid":false,"given":"James E.","family":"Dahlman","sequence":"additional","affiliation":[{"name":"2Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3268-5759","authenticated-orcid":false,"given":"Jeroen C. 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A fundamental building block of RNA structure crucial to RNA function in diverse biological systems","volume":"1","author":"Varani","year":"2000","journal-title":"EMBO Rep"},{"issue":"15","key":"2023102319205641800_bib38","doi-asserted-by":"crossref","first-page":"4704","DOI":"10.1093\/nar\/gki785","article-title":"Tolerated wobble mutations in siRNAs decrease specificity, but can enhance activity in\u00a0vivo","volume":"33","author":"Holen","year":"2005","journal-title":"Nucleic Acids Res"},{"issue":"8","key":"2023102319205641800_bib39","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1111\/j.1538-7836.2012.04797.x","article-title":"Contribution of platelet vs. endothelial VWF to platelet adhesion and hemostasis","volume":"10","author":"Kanaji","year":"2012","journal-title":"J\u00a0Thromb Haemost"},{"key":"2023102319205641800_bib40","doi-asserted-by":"crossref","first-page":"26306","DOI":"10.1038\/srep26306","article-title":"A\u00a0genetically-engineered von Willebrand disease type 2B mouse model displays defects in hemostasis and inflammation","volume":"6","author":"Adam","year":"2016","journal-title":"Sci Rep"},{"key":"2023102319205641800_bib41","doi-asserted-by":"crossref","unstructured":"Jongejan\n              YK DR\n            , de JongA, van VlijmenBJM, EikenboomJCJ. Identification of small interfering RNAs for allele-selective silencing of murine von Willebrand factor. Paper presented at: ISTH 2021 Congress; June 2021; Philadelphia, PA. Accessed 7 September 2022. https:\/\/abstracts.isth.org\/abstract\/identification-of-small-interfering-rnas-for-allele-selective-silencing-of-murine-von-willebrand-factor\/.","DOI":"10.1182\/bloodadvances.2023010643"}],"container-title":["Blood Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article-pdf\/7\/20\/6108\/2085351\/blooda_adv-2023-010643-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article-pdf\/7\/20\/6108\/2085351\/blooda_adv-2023-010643-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T19:21:45Z","timestamp":1698088905000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article\/7\/20\/6108\/496898\/Small-interfering-RNA-mediated-allele-selective"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,12]]},"references-count":41,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2023,10,24]]}},"URL":"https:\/\/doi.org\/10.1182\/bloodadvances.2023010643","relation":{},"ISSN":["2473-9529","2473-9537"],"issn-type":[{"value":"2473-9529","type":"print"},{"value":"2473-9537","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,12]]}}}