{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T01:28:40Z","timestamp":1789176520834,"version":"build-2803163510"},"reference-count":42,"publisher":"American Society of Hematology","issue":"13","license":[{"start":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T00:00:00Z","timestamp":1720742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,9,26]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Rondaptivon pegol (previously BT200) is a pegylated RNA aptamer that binds to the A1 domain of von Willebrand factor (VWF). Recent clinical trials demonstrated that BT200 significantly increased plasma VWF\u2013factor VIII levels by attenuating VWF clearance. The biological mechanism(s) through which BT200 attenuates in\u00a0vivo clearance of VWF has not been defined. We hypothesized that BT200 interaction with the VWF-A1 domain may increase plasma VWF levels by attenuating macrophage-mediated clearance. We observed that full-length and VWF-A1A2A3 binding to macrophages and VWF-A1 domain binding to lipoprotein receptor\u2013related protein 1 (LRP1) cluster II and cluster IV were concentration-dependently inhibited by BT200. Additionally, full-length VWF binding to LRP1 expressed on HEK293T (HEK-LRP1) cells was also inhibited by BT200. Importantly, BT200 interacts with the VWF-A1 domain in proximity to a conserved cluster of 4 lysine residues (K1405, K1406, K1407, and K1408). Alanine mutagenesis of this K1405-K1408 cluster (VWF-4A) significantly (P\u00a0&amp;lt; .001) attenuated binding of VWF to both LRP1 clusters II and IV. Furthermore, in\u00a0vivo clearance of VWF-4A was significantly (P\u00a0&amp;lt; .001) reduced than that of wild-type VWF. BT200 did not significantly inhibit binding of VWF-4A to LRP1 cluster IV or HEK-LRP1 cells. Finally, BT200 interaction with the VWF-A1 domain also inhibited binding to macrophage galactose lectin and the SR-AI scavenger receptor. Collectively, our findings demonstrate that BT200 prolongs VWF half-life by attenuating macrophage-mediated clearance and specifically the interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1. These data support the concept that targeted inhibition of VWF clearance pathways represents a novel therapeutic approach for von Willebrand disease and hemophilia A.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024024055","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T16:04:03Z","timestamp":1720800243000},"page":"1445-1456","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":23,"title":["The aptamer BT200 blocks interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1"],"prefix":"10.1182","volume":"144","author":[{"given":"Alain","family":"Chion","sequence":"first","affiliation":[{"name":"1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-0644","authenticated-orcid":false,"given":"Ciara","family":"Byrne","sequence":"additional","affiliation":[{"name":"1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3769-9148","authenticated-orcid":false,"given":"Ferdows","family":"Atiq","sequence":"additional","affiliation":[{"name":"1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9759-062X","authenticated-orcid":false,"given":"Dearbhla","family":"Doherty","sequence":"additional","affiliation":[{"name":"1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5794-5177","authenticated-orcid":false,"given":"Sonia","family":"Aguila","sequence":"additional","affiliation":[{"name":"1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"},{"name":"2Centro Regional de Hemodonaci\u00f3n, Hospital Universitario Morales Meseguer, IMIB-Arrixaca, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judicael","family":"Fazavana","sequence":"additional","affiliation":[{"name":"1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9287-5354","authenticated-orcid":false,"given":"Patricia","family":"Lopes","sequence":"additional","affiliation":[{"name":"1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-076X","authenticated-orcid":false,"given":"Ellie","family":"Karampini","sequence":"additional","affiliation":[{"name":"1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aamir","family":"Amin","sequence":"additional","affiliation":[{"name":"1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0108-4077","authenticated-orcid":false,"given":"Roger J. 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