Preclinical safety and bleeding evaluation in swine for a small interfering RNA-lipid nanoparticle that prevents excess fibrinogen synthesis.

BACKGROUND

Fibrinogen levels can drastically increase from inflammation, trauma, or surgery, which increases 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).

OBJECTIVES

This study evaluated the preclinical safety and feasibility of a novel therapy for VTE prophylaxis for complications in trauma and surgical patients.

METHODS

Female Yorkshire/cross swine (7-15 kg) were infused with small interfering RNA targeting fibrinogen (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 concentrations decreased in swine in a dose-dependent manner, lasting over a week from 1 injection of siFibrinogen. Fibrinogen reduction to levels > 0.4 g/L did not impair hemostasis during hemorrhagic shock when compared with LMWH or vehicle control. The effects of siFibrinogen were reversed by the administration of fibrinogen concentrate. No infusion-related reactions or toxicity was observed.

CONCLUSION

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.