Session: 321. Coagulation and Fibrinolysis: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Bleeding and Clotting, Bleeding disorders, Translational Research, Hemophilia, Diseases, VWD
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.
Disclosures: Strilchuk: SeraGene Therapeutics Inc: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Juang: SeraGene Therapeutics Inc: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Kastrup: SeraGene Therapeutics Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; NanoVation Therapeutics Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; CoMotion Drug Delivery Systems: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Consultancy.
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