Preclinical safety and bleeding evaluation in swine for an siRNA-lipid nanoparticle that prevents excess fibrinogen synthesis

Abstract

Background: Fibrinogen levels can drastically increase from inflammation, trauma, or surgery, which drives an increased risk of venous thromboembolism (VTE). We developed small interfering RNA (siFibrinogen) that decreased fibrinogen production and thrombosis in rodent models, which became effective hours after administration and knockdown lasted over a week. Here, we tested whether knockdown of fibrinogen was feasible and safe in a preclinical large animal model. We hypothesized that fibrinogen could be controllably knocked down to levels that still enable hemostasis and avoid limitations of the current standard of care agent, low molecular weight heparin (LMWH).

Objective: Toward preventing complications in trauma and surgical patients, this study evaluated the preclinical safety and feasibility of a novel therapy for venous thromboembolism (VTE) prophylaxis.

Methods: Female Yorkshire/cross swine (7-15 kg) were infused with siFibrinogen, LMWH, or a vehicle control. Hemostasis was assessed in an established model of hemorrhagic shock. Reversibility was evaluated by administering fibrinogen concentrate.

Results: Circulating fibrinogen decreased in swine in a dose-dependent manner, lasting over a week from one injection of siFibrinogen. Fibrinogen reduction to levels above 0.4 g/L did not impair hemostasis during hemorrhagic shock when compared to LMWH or vehicle control. The effects of siFibrinogen were reversed with the administration of fibrinogen concentrate. No infusion-related reactions or toxicity was observed.

Conclusions: siFibrinogen represents a promising novel approach for VTE prophylaxis, avoiding limitations of LMWH. siFibrinogen administered early in patient care could decrease fibrinogen in a sustained and predictable manner to prevent thrombosis while preserving hemostasis.