Antithrombin inhibition using nanobodies to correct bleeding in hemophilia

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 ( RNA i) 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 AAV 8‐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 .