Saturday, May 3, 2025
5/3/2025
Targeting inflammation and oxidative stress to treat acute lung injury with CNP-miR146a - SUMMARY Acute respiratory distress syndrome (ARDS) accounts for 10% of ICU admissions worldwide, with a mortality as high as 46%. ARDS incidence has risen dramatically during the COVID-19 pandemic. Despite improvements in critical care and early detection of lung injury, the management of ARDS remains largely supportive. Although mechanical ventilation may provide the necessary life support, impaired pulmonary mechanics and subsequent ventilator induced lung injury (VILI) can impose a second insult that worsens outcomes. A range of insults, including trauma, sepsis, pulmonary infections, or toxin exposure, are associated with acute lung injury (ALI) and the subsequent development of a systemic inflammatory response and progression to ARDS, leading to alterations in lung compliance and lung fibrosis. A central pathogenic feature of ARDS is the persistent activation of inflammation and oxidative stress. Following ALI, lung macrophages produce pro-inflammatory cytokines that result in the recruitment of additional inflammatory cells and the generation of reactive oxygen species (ROS). Persistent amplification of inflammation and oxidative stress leads to the progression to ARDS, promotion of long-term fibrosis and morbidity. Ceria Therapeutics is developing a novel therapeutic product, CTX-002, that synergistically targets both inflammation and oxidative stress. CTX-002 (CNP-miR146a) is a cerium oxide nanoparticle (CNP), which possess ROS scavenging properties, conjugated with an anti-inflammatory miR146a mimetic to target both ROS and the inflammatory response. Supported by a Phase I application, we have demonstrated that a single administration of CTX-002 can prevent bleomycin, MRSA, and lipopolysaccharide-induced inflammation and lung injury, even when administered three or seven days after injury. In addition, treatment with CTX-002 resulted in improved pulmonary mechanics and prevention of subsequent VILI. We also demonstrated that systemic intravenous single and repeat-dose administration of up to 10-fold the intended clinical dose of CTX-002 showed no signs of toxicity in rats. The objectives of this Phase II proposal are to 1) determine pulmonary distribution of CTX-002 in pigs to demonstrate that intratracheal administration of the drug results in no systemic exposure of CTX-002 but increased concentration in the lungs; 2) scale-up synthesis and complete analytical characterization, formulation and stability of CTX-002; 3) perform GLP-compliant safety and toxicology studies in rats and pigs. To complete this Phase II application, we will prepare and submit an IND for clearance to begin first-in-human clinical trials of CTX-002 for ARDS.
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