Intravenous Delivery of Long-Acting Dnase I (PRX-119) In a Murine Model of Polymicrobial Abdominal Sepsis.

Abstract

OBJECTIVE: Sepsis is a life-threatening complication of infection in which a dysregulated host response precipitates multiorgan dysfunction. Neutrophil extracellular traps contribute to infection-induced immunothrombosis by releasing cell-free DNA (cfDNA), which provides a prothrombotic scaffold for blood clots. Although DNase I has therapeutic promise due to its ability to degrade cfDNA, its short plasma half-life (2 to 4 h) may necessitate multiple daily injections, potentially posing challenges for clinical use. This study investigates the efficacy of i.v. administration of PRX-119, a PEGylated recombinant human DNase I with an extended half-life of ~12 h. METHODS: Sepsis was induced in C57Bl/6 mice (10-12 weeks old) using the cecal ligation and puncture (CLP) model. The efficacy of i.v. PRX-119 (1 mg/kg) was tested in 72-h and 7-day survival studies, including clinically relevant supportive therapies (antibiotics, fluid resuscitation). We measured plasma levels of cfDNA, IL-6, IL-10, and thrombin-antithrombin (TAT) complexes. We assessed physiological parameters, bacterial burden, lung myeloperoxidase, and organ injury/function. RESULTS: Using both sexes, a single dose of PRX-119 (at T  = 8 h) or two doses (at T  = 4 and 24 h) improved survival at 72 h. Using male mice, we observed that three doses (at T  = 4, 20, and 36 post-CLP) provided a sustained protective effect at 7 days post-CLP. PRX-119 treatment reduced cfDNA, IL-6, TAT, lung myeloperoxidase, and bacterial load. PRX-119 treatment also reduced organ injury. CONCLUSIONS: Intravenous delivery of PRX-119 improved survival and reduced immunothrombosis and organ injury, without the need for frequent injections.