In this issue of EMBO Molecular Medicine, Barbon et al describe a new approach to rebalancing coagulation in patients with hemophilia (PWH) through targeted inhibition of anticoagulant antithrombin (AT) (Barbon et al, 2020). In contrast to previous studies that used RNA interference (RNAi) therapy to reduce AT levels (Sehgal et al, 2015; Pasi et al, 2017), the authors utilized llama-derived single-domain antibodies (sdAbs or nanobodies) to inhibit AT activity (Fig 1). These engineered sdAbs successfully restored thrombin generation in hemophilic plasma and corrected bleeding phenotype in a murine hemophilia model. Furthermore, long-term AAV8-mediated hepatic expression of the sdAb was well tolerated and associated with a sustained correction in bleeding in hemophilia A and B mice. Collectively, these exciting data uncover a novel AT-targeting approach that may be useful as an alternative therapy for restoring normal hemostasis in PWH.

中文翻译：

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使用纳米抗体抑制凝血酶，以纠正血友病中​​的出血。

在本期《 EMBO分子医学》中，Barbon等人描述了一种通过靶向抑制抗凝抗凝血酶（AT）来重新平衡血友病患者（PWH）凝血的新方法（Barbon等人，2020年）。与之前使用RNA干扰（RNAi）治疗降低AT水平的研究相反（Sehgal等，2015; Pasi等，2017），作者利用骆驼衍生的单域抗体（sdAb或纳米抗体）抑制AT活性（图。1）。这些工程改造的sdAb成功地恢复了血友病血浆中的凝血酶生成，并纠正了鼠血友病模型中的出血表型。此外，对sdAb的长期AAV8介导的肝表达具有良好的耐受性，并且与血友病A和B小鼠的出血持续纠正有关。总的来说，