Intravenous Delivery of Long-Acting Dnase I (PRX-119) In a Murine Model of Polymicrobial Abdominal Sepsis
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".