A Therapeutic siRNA Targeting Plasminogen Acts As a Long-Lasting Antifibrinolytic in Nonhuman Primates

To maintain hemostasis while preventing thrombosis, clot formation must be tightly regulated by the coagulation, anticoagulation, and fibrinolytic systems. Fibrinolysis, the proteolytic process that degrades and clears blood clots from the vasculature, becomes activated both during and after clot formation, opposing the growth of the fibrin clot and ultimately restoring blood flow through vessels. In conditions where coagulation is compromised, the balance between clot formation and degradation is disrupted. When coagulation is weaker, fibrinolysis is more active, and these combined pressures lead to impaired hemostasis. Antifibrinolytic drugs, such as tranexamic acid (TXA), are used on-demand to achieve hemostasis in diverse clinical scenarios, including heavy menstrual bleeding, prehospital trauma, surgical hemorrhage, and bleeding disorders. Suppressing fibrinolysis could also prevent or lessen the chronic recurring bleeding caused by bleeding disorders, but current small molecule antifibrinolytics are cleared too rapidly to maintain stable inhibition. We are investigating the use of small interfering RNA (siRNA) targeting the central fibrinolytic protein, plasminogen, as a long-lasting antifibrinolytic that can restore the balance between coagulation and fibrinolysis to achieve hemostasis in bleeding disorders. Previously, species-specific siRNA targeting plasminogen (siPLG) achieved fibrinolytic suppression in wild-type mice and dogs, performing as well as TXA, without causing any symptoms associated with plasminogen deficiency after months of knockdown. In hemophilia A mice, pre-treatment with siPLG reduced the severity of induced bleeds. In hemophilia A dogs, repeat dosing with siPLG over a 4-month period reduced the frequency of spontaneous bleeding episodes. In this work, we investigate the ability of a human compatible siPLG to knock down plasminogen and suppress fibrinolysis in nonhuman primates. Intravenous administration of siPLG contained in lipid nanoparticles achieved 70% knockdown of circulating plasminogen at doses as low as 0.1 mg siRNA / kg body weight. Knockdown lasted for weeks after administration, and thromboelastometry showed that clots had increased stability during this time. All doses tested (up to 0.3 mg/kg) were well tolerated, with no changes in complete blood count or markers of liver and kidney function. Animals were monitored for adverse effects or symptoms of plasminogen deficiency, and menses were tracked to evaluate the impact of siPLG on menstrual bleeding. TXA is often recommended for people experiencing heavy menstrual bleeding, and is effective irrespective of the underlying cause of bleeding because it restores the balance between coagulation and fibrinolysis. This siRNA strategy is predicted to be effective in the many indications where TXA is used, and has the potential to overcome many of the limitations of current prophylactics for bleeding disorders, such as frequent administration, thrombotic risk, and applicability to those with inhibitory antibodies.

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