STC3141 improves acute lung injury through neutralizing circulating histone in rat with experimentally-induced acute respiratory distress syndrome

Ge, Yangyang; Wang, Chenchen; Yao, Cong; Wang, Yong; Zheng, Yuduo; Luo, Junjie; Chen, Jiayi; Wang, Ye; Wang, Fuquan; Wang, Li; Lin, Yun; Shi, Lin; Yao, Shanglong

doi:10.3389/fphar.2023.1166814

Cited by 6 publications

(1 citation statement)

References 39 publications

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“…Compared with systemic administration, it allows for targeted delivery of medication directly to the lungs by passing the gastrointestinal tract or liver and avoiding potential side effects associated with systemic administration. Additionally, this method can achieve higher concentrations of medication in the lungs, which may be particularly beneficial for treating localized respiratory infections or inflammation. − Next, we administered equal amounts of MSC-EVs-PD-L1 to ARDS model mice using both intravenous and intratracheal administration (Figure a). After 8 h of injection, lungs were collected and imaged by an in vivo imaging system.…”

Section: Resultsmentioning

confidence: 99%

PD-L1-Expressing Extracellular Vesicles for the Treatment of Pneumonia

Wu,

Wang,

Song

et al. 2023

ACS Biomater. Sci. Eng.

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Acute respiratory distress syndrome (ARDS) is a severe lung condition with a high mortality rate and a lack of effective drug therapy. In this work, we developed mesenchymal stem cell (MSC)-derived extracellular vesicles with high PD-L1 expression (MSC-EVs-PD-L1) for treating lipopolysaccharide (LPS)-induced pneumonia by intratracheal administration. We found an upregulation of PD-1 expression in the inflammatory region of murine lungs; hence, MSC-EVs-PD-L1 exerted immunosuppressive effects via the PD-1/PD-L1 signaling pathway. Furthermore, we treated LPS-induced pneumonia mice by intratracheal administration, which enabled heavy drug accumulation in the lungs of mice and better therapeutic efficacy compared to systemic administration. Our results suggest that MSC-EVs-PD-L1 has the potential to provide a universal platform technology for the immunotherapy of pneumonia.

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Section: Resultsmentioning

confidence: 99%

PD-L1-Expressing Extracellular Vesicles for the Treatment of Pneumonia

Wu,

Wang,

Song

et al. 2023

ACS Biomater. Sci. Eng.

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The pathogenesis and potential therapeutic targets in sepsis

Zhang,

Jiang,

et al. 2023

MedComm

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Sepsis is defined as “a life‐threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection.” At present, sepsis continues to pose a grave healthcare concern worldwide. Despite the use of supportive measures in treating traditional sepsis, such as intravenous fluids, vasoactive substances, and oxygen plus antibiotics to eradicate harmful pathogens, there is an ongoing increase in both the morbidity and mortality associated with sepsis during clinical interventions. Therefore, it is urgent to design specific pharmacologic agents for the treatment of sepsis and convert them into a novel targeted treatment strategy. Herein, we provide an overview of the molecular mechanisms that may be involved in sepsis, such as the inflammatory response, immune dysfunction, complement deactivation, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we highlight important targets involved in sepsis‐related regulatory mechanisms, including GSDMD, HMGB1, STING, and SQSTM1, among others. We summarize the latest advancements in potential therapeutic drugs that specifically target these signaling pathways and paramount targets, covering both preclinical studies and clinical trials. In addition, this review provides a detailed description of the crosstalk and function between signaling pathways and vital targets, which provides more opportunities for the clinical development of new treatments for sepsis.

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A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis

Bellomo,

Patava,

Van Lancker

et al. 2024

Pharmacology Res & Perspec

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Increased circulating histones correlate with sepsis severity and are a potential therapeutic target. Pre‐clinical studies showed benefit with a histone‐neutralizing polyanion molecule (STC3141). We aimed to investigate the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis. We studied 26 patients with sepsis divided into four cohorts of one, five, ten, and ten subjects, respectively. We conducted a dose‐adjusted, open‐label study to determine the safety, tolerability, and pharmacokinetics of STC3141 administered as an IV infusion for up to 72 h, with rate adjusted to estimated creatinine clearance. Four steady‐state concentrations were targeted. Twenty of the 26 subjects (77%) in the study experienced at least one adverse event (AE). The most frequently reported study drug‐related AE was a mildly prolonged aPTT (four events). Only one AE (pulmonary hemorrhage) led to discontinuation of the drug. After excluding patients receiving renal replacement therapy (RRT) patients, clearance ranged from 3.3 to 4.2 L/h across cohorts and was essentially completely renal in nature. Half‐life values ranged from 5 to 7 h. The mean (±SD) terminal half‐life for non‐RRT subjects and for whom it was possible to calculate was approximately 9 (±4.77) h but increased to 19 (±7.94) h for subjects on RRT. Overall, 18 (69.2%) patients completed the study to day eight in the ICU, and 22 (84.6%) survived to 28 days. STC3141 administration appeared to have an acceptable degree of safety and tolerability and expected pharmacokinetics. Cautious, larger randomized efficacy trials in sepsis appear justified.

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STC3141 improves acute lung injury through neutralizing circulating histone in rat with experimentally-induced acute respiratory distress syndrome

Cited by 6 publications

References 39 publications

PD-L1-Expressing Extracellular Vesicles for the Treatment of Pneumonia

PD-L1-Expressing Extracellular Vesicles for the Treatment of Pneumonia

The pathogenesis and potential therapeutic targets in sepsis

A dose‐adjusted, open‐label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis

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