Small interfering RNA targeting protein Z-dependent protease inhibitor improves hemostasis in Von Willebrand factor- and Factor X-deficient mice.

Non-factor therapeutics have transformed the treatment paradigm in hemophilia A. Owing to their mode of action, these agents may also provide benefit for other rare bleeding disorders (RBDs) such as von Willebrand disease (VWD)-type 3 and Factor X (FX) deficiency. Targeting protein Z-dependent protease inhibitor (ZPI), a natural anticoagulant, is a novel strategy to enhance hemostasis. We evaluated the effects of ZPI post-transcriptional silencing using a GalNAc-conjugated siRNA (mTGM-148) in von Willebrand factor-deficient (VwfKO) mice and in mice with strongly reduced factor X levels (< 1%; f10low-mice). mTGM-148 reduced plasma ZPI antigen below 15% in both models. In VwfKO-mice, mTGM-148 significantly enhanced contact activation-initiated thrombin generation and normalized INTEM clotting parameters. In f10low-mice, thrombin generation was minimally affected, but EXTEM clotting parameters were significantly ameliorated. Importantly, mTGM-148 treatment significantly reduced blood loss in the tail clip model for both VwfKO-mice and f10low-mice. These data suggest that ZPI post-transcriptional silencing is a viable strategy to improve the hemostatic potential in both VWD-type 3 and FX deficiency. As such, ZPI inhibition represents a promising non-factor therapeutic approach for selected RBDs.