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 machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".