Intravenous delivery of long-acting DNase I (PRX-119) in a murine model of polymicrobial abdominal sepsis.
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OBJECTIVE: Sepsis is a life-threatening complication of infection in which a dysregulated host response precipitates multi-organ dysfunction. Neutrophil extracellular traps (NETs) 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 hours) may necessitate multiple daily injections, potentially posing challenges for clinical use. This study investigates the efficacy of intravenous administration of PRX-119, a PEGylated recombinant human DNase I with an extended half-life of ~12 hours. METHODS: Sepsis was induced in C57Bl/6 mice (10 to 12 weeks old) using the cecal ligation and puncture (CLP) model. The efficacy of intravenous PRX-119 (1 mg/kg) was tested in 72-hour 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 (MPO), and organ injury/function. RESULTS: Using both sexes, a single dose of PRX-119 (at T = 8 hours) or two doses (at T = 4 and T = 24 hours) improved survival at 72 hours. Using male mice, we observed that three doses (at T = 4 h, 20 h, and 36 h post-CLP) provided a sustained protective effect at 7 days post-CLP. PRX-119 treatment reduced cfDNA, IL-6, TAT, lung MPO, 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.
