A neutralizable dimeric anti-thrombin aptamer with potent anticoagulant activity in mice

• Published in: Molecular therapy. Nucleic acids 2023-09, Vol.33, p.762-772
• Main Authors: Nagano, Masanobu, Kubota, Kazuki, Sakata, Asuka, Nakamura, Rei, Yoshitomi, Toru, Wakui, Koji, Yoshimoto, Keitaro
• Format: Article
• Language: English
• Subjects: antidote; aptamer; avidity; bivalent aptamer; circular aptamer; heparin-induced thrombocytopenia; iv injection; MT: Oligonucleotides: Therapies and Applications; Original; TBA29; thrombin
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2023.07.038

Heparin-induced thrombocytopenia (HIT) is a complication caused by administration of the anticoagulant heparin. Although the number of patients with HIT has drastically increased because of coronavirus disease 2019 (COVID-19), the currently used thrombin inhibitors for HIT therapy do not have antidotes to arrest the severe bleeding that occurs as a side effect; therefore, establishment of safer treatments for HIT patients is imperative. Here, we devised a potent thrombin inhibitor based on bivalent aptamers with a higher safety profile via combination with the antidote. Using an anti-thrombin DNA aptamer M08s-1 as a promising anticoagulant, its homodimer and heterodimer with TBA29 linked by a conformationally flexible linker or a rigid duplex linker were designed. The dimerized M08s-1-based aptamers had about 100-fold increased binding affinity to human and mouse thrombin compared with the monomer counterparts. Administration of these bivalent aptamers into mice revealed that the anticoagulant activity of the dimers significantly surpassed that of an approved drug for HIT treatment, argatroban. Moreover, adding protamine sulfate as an antidote against the most potent bivalent aptamer completely suppressed the anticoagulant activity of the dimer. Emerging potent and neutralizable anticoagulant aptamers will be promising candidates for HIT treatment with a higher safety profile. [Display omitted] Yoshimoto and colleagues report a highly potent anticoagulant aptamer in mice. A bivalent aptamer dimerized with M08s-1 showed potent anticoagulant activity in mice, and an antidote could reverse the activity. This aptamer may be an alternative to current drugs for patients with heparin-induced thrombocytopenia drastically increased by COVID-19.