ArticleBlood2024
The aptamer BT200 blocks interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1.
Article in Blood, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Novel therapies for von Willebrand disease.Blood advances · 2026Review
- Von Willebrand Factor as a Therapeutic Target in Thrombotic Disorders.Thrombosis and haemostasis · 2026Review
- Monovalent antibody treatment of von Willebrand disease.Blood advances · 2026Article
- HMB-002: a monovalent antibody that elevates circulating VWF and FVIII levels for treatment of von Willebrand disease.Blood advances · 2026Article
- Gynecologic and obstetric management of girls and women with von Willebrand disease.Haematologica · 2026Review
- Advancements in SELEX Technology for Aptamers and Emerging Applications in Therapeutics and Drug Delivery.Biomolecules · 2025Review
- Using RNA therapeutics to promote healthy aging.Nature aging · 2025Review
- Prophylaxis in von Willebrand disease with von Willebrand factor concentrate and nonfactor therapies.Research and practice in thrombosis and haemostasis · 2024Article
- Conformation-specific RNA aptamers for phenotypic distinction between normal von Willebrand factor and type 2B von Willebrand disease.NAR molecular medicine · 2024Article
- Brevianamide F Exerts Antithrombotic Effects by Modulating the MAPK Signaling Pathway and Coagulation Cascade.Marine drugs · 2024Article
- von Willebrand disease.Nature reviews. Disease primers · 2024Review
Corrections and comments
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Authors and funding
17 authors.
Funding
Abstract
abstractRondaptivon 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-factor VIII levels by attenuating VWF clearance. The biological mechanism(s) through which BT200 attenuates in vivo 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-related 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 < .001) attenuated binding of VWF to both LRP1 clusters II and IV. Furthermore, in vivo clearance of VWF-4A was significantly (P < .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.
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