| Title: |
Lipid nanoparticles and siRNA targeting plasminogen provide lasting inhibition of fibrinolysis in mouse and dog models of hemophilia A. |
| Authors: |
Strilchuk, Amy W.; Hur, Woosuk S.; Batty, Paul; Sang, Yaqiu; Abrahams, Sara R.; Yong, Alyssa S.M.; Leung, Jerry; Silva, Lakmali M.; Schroeder, Jocelyn A.; Nesbitt, Kate; de Laat, Bas; Moutsopoulos, Niki M.; Bugge, Thomas H.; Shi, Qizhen; Cullis, Pieter R.; Merricks, Elizabeth P.; Wolberg, Alisa S.; Flick, Matthew J.; Lillicrap, David; Nichols, Timothy C. |
| Source: |
Science Translational Medicine; 2/21/2024, Vol. 16 Issue 735, p1-9, 9p |
| Subject Terms: |
Plasminogen; Fibrinolysis; Small interfering RNA; Laboratory mice; Saphenous vein; Tranexamic acid |
| Abstract: |
Antifibrinolytic drugs are used extensively for on-demand treatment of severe acute bleeding. Controlling fibrinolysis may also be an effective strategy to prevent or lessen chronic recurring bleeding in bleeding disorders such as hemophilia A (HA), but current antifibrinolytics have unfavorable pharmacokinetic profiles. Here, we developed a long-lasting antifibrinolytic using small interfering RNA (siRNA) targeting plasminogen packaged in clinically used lipid nanoparticles (LNPs) and tested it to determine whether reducing plasmin activity in animal models of HA could decrease bleeding frequency and severity. Treatment with the siRNA-carrying LNPs reduced circulating plasminogen and suppressed fibrinolysis in wild-type and HA mice and dogs. In HA mice, hemostatic efficacy depended on the injury model; plasminogen knockdown improved hemostasis after a saphenous vein injury but not tail vein transection injury, suggesting that saphenous vein injury is a murine bleeding model sensitive to the contribution of fibrinolysis. In dogs with HA, LNPs carrying siRNA targeting plasminogen were as effective at stabilizing clots as tranexamic acid, a clinical antifibrinolytic, and in a pilot study of two dogs with HA, the incidence of spontaneous or excess bleeding was reduced during 4 months of prolonged knockdown. Collectively, these data demonstrate that long-acting antifibrinolytic therapy can be achieved and that it provides hemostatic benefit in animal models of HA. Editor's summary: Patients with hemophilia A suffer from spontaneous and excessive bleeding that can be treated with antifibrinolytics, but the short half-life of such drugs limits their use to on-demand treatment. Here, Strilchuk and colleagues packaged small interfering RNAs against plasminogen into lipid nanoparticles, showing that a single dose could reduce circulating plasminogen and suppress fibrinolysis for several weeks in mice. Prophylactic treatment led to improved hemostasis after saphenous vein injury in a mouse model of hemophila A, and 4 months of plasminogen knockdown decreased spontaneous and excess bleeding events in two dogs with hemophilia A without evidence of severe toxicity, suggesting that this approach should be further studied in the context of hemophilia A and other diseases characterized by high fibrinolysis. —Melissa L. Norton [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |