{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:35:52Z","timestamp":1788568552554,"version":"build-2803163510"},"reference-count":35,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,1,28]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Treatment options for the bleeding disorder von Willebrand disease type 2B (VWD2B) are insufficient and fail to address the negative effects of circulating mutant von Willebrand factor (VWF). The dominant-negative nature of VWD2B makes functionally defective VWF an interesting therapeutic target. Previous in\u00a0vitro studies have demonstrated the feasibility of allele-selective silencing of mutant VWF using small interfering RNAs (siRNAs) targeting common single nucleotide polymorphisms (SNPs) in the human VWF gene, an approach that can be applied irrespective of the disease-causing VWF mutation. This study aims to extend this concept to a heterozygous VWD2B mouse model (c.3946G&amp;gt;A; p.Val1316Met) here using mouse strain-specific genetic differences as proxy for human SNPs. Homozygous VWD2B C57BL\/6J (2B-B6) mice were crossed with homozygous wild-type 129S1\/SvImJ (129S) mice to create heterozygous 2B-B6.129S F1 offspring. These 2B-B6.129S mice were intravenously injected with endothelial-specific lipid nanoparticles loaded with the allele-selective siVwf.B6 or control and 96 hours later, lung Vwf messenger RNA, plasma VWF levels, and phenotypic characteristics were evaluated. Treatment with siVwf.B6 reduced total VWF levels by 50%, with an expected selective reduction in mutant VWF protein. This coincided with normalization of multimeric structure, improved VWF collagen binding\/VWF antigen ratio, and normalized bleeding times in two-thirds of heterozygous 2B-B6.129S mice. Being a novel approach in the field of hemostasis, we proved, for VWD, in mice, the concept of selectively inhibiting a mutant dominant-negative allele with siRNAs targeting a single nucleotide variation rather than the disease-causing mutation. For dominant-negative VWD, this offers potential for a customized therapeutic strategy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/bloodadvances.2024014601","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T16:30:55Z","timestamp":1737045055000},"page":"310-320","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":12,"title":["Amelioration of a von Willebrand disease type 2B phenotype in\u00a0vivo upon treatment with allele-selective siRNAs"],"prefix":"10.1182","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8819-3446","authenticated-orcid":false,"given":"Noa A.","family":"Linthorst","sequence":"first","affiliation":[{"name":"1Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1118-7005","authenticated-orcid":false,"given":"Yvonne K.","family":"Jongejan","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9626-9925","authenticated-orcid":false,"given":"Richard J.","family":"Dirven","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9206-8712","authenticated-orcid":false,"given":"Sebastiaan N. J.","family":"Laan","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"2Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1205-9689","authenticated-orcid":false,"given":"Ruben","family":"Bierings","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8271-6795","authenticated-orcid":false,"given":"Caterina","family":"Casari","sequence":"additional","affiliation":[{"name":"3Laboratory for Hemostasis, Inflammation and Thrombosis, Unit\u00e9 Mixed de Recherche S1176, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Universit\u00e9 Paris-Saclay, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7200-7434","authenticated-orcid":false,"given":"Robert A.","family":"Cordfunke","sequence":"additional","affiliation":[{"name":"4Department of Immunology, 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":"5Wallace 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\/0009-0003-5072-1455","authenticated-orcid":false,"given":"Natasja","family":"Dolezal","sequence":"additional","affiliation":[{"name":"4Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4808-5296","authenticated-orcid":false,"given":"Jan Wouter","family":"Drijfhout","sequence":"additional","affiliation":[{"name":"4Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5677-1371","authenticated-orcid":false,"given":"Frank W. 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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\/0000-0003-4585-2621","authenticated-orcid":false,"given":"Jan","family":"Voorberg","sequence":"additional","affiliation":[{"name":"7Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-6453","authenticated-orcid":false,"given":"Bart J. 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