Faculty Collaboration Database

Lipid nanoparticles and siRNA targeting plasminogen provide lasting inhibition of fibrinolysis in mouse and dog models of hemophilia A. Sci Transl Med 2024 Feb 21;16(735):eadh0027

Date

02/21/2024

Pubmed ID

38381848

Pubmed Central ID

PMC11293256

DOI

10.1126/scitranslmed.adh0027

Scopus ID

2-s2.0-85185823776 (requires institutional sign-in at Scopus site)   6 Citations

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.

Author List

Strilchuk AW, Hur WS, Batty P, Sang Y, Abrahams SR, Yong ASM, Leung J, Silva LM, Schroeder JA, Nesbitt K, de Laat B, Moutsopoulos NM, Bugge TH, Shi Q, Cullis PR, Merricks EP, Wolberg AS, Flick MJ, Lillicrap D, Nichols TC, Kastrup CJ

Authors

Christian Kastrup PhD Professor in the Surgery department at Medical College of Wisconsin
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antifibrinolytic Agents
Dogs
Fibrinolysis
Hemophilia A
Hemorrhage
Hemostatics
Liposomes
Mice
Nanoparticles
Pilot Projects
Plasminogen
RNA, Small Interfering