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 (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.