Targeting inflammation and oxidative stress to treat acute lung injury with CNP-miR146a

总结 急性呼吸窘迫综合征（ARDS）占全世界ICU入院人数的10%，死亡率为 高达46%。在COVID-19大流行期间，ARDS发病率急剧上升。尽管有所改善 在重症监护和肺损伤的早期检测中，ARDS的治疗仍然是主要的支持。虽然 机械通气可以提供必要的生命支持， 呼吸机诱导的肺损伤（VILI）可造成第二次损伤，从而影响预后。一系列的侮辱， 包括创伤、败血症、肺部感染或毒素暴露，与急性肺损伤（ALI）相关， 随后发生全身炎症反应并进展为ARDS，导致 肺顺应性和肺纤维化的改变。急性呼吸窘迫综合征的一个重要致病特征是持续性激活 炎症和氧化应激。ALI后，肺巨噬细胞产生促炎细胞因子， 导致额外炎性细胞的募集和活性氧（ROS）的产生。 炎症和氧化应激的持续放大导致向ARDS的进展， 长期纤维化和发病率。 Ceria Therapeutics正在开发一种新型治疗产品CTX-002， 炎症和氧化应激。CTX-002（CNP-miR 146 a）是氧化铈纳米颗粒（CNP），其 具有ROS清除特性，与抗炎miR 146 a模拟物缀合，以靶向ROS 和炎症反应。在第一阶段应用程序的支持下，我们已经证明， CTX-002的施用可以预防博来霉素、MRSA和脂多糖诱导的炎症， 肺损伤，即使在受伤后三天或七天给药。此外，用CTX-002治疗导致 改善肺力学和预防随后的VILI。我们还证明，系统 静脉单次和重复给药高达CTX-002预期临床剂量的10倍，显示 大鼠中无毒性迹象。本II期提案的目标是：1）确定 CTX-002在猪中的应用，以证明药物的腹膜内给药不会导致CTX-002的全身暴露。 CTX-002，但在肺中的浓度增加; 2）放大合成和完整的分析 CTX-002的表征、配制和稳定性; 3）进行符合GLP的安全性和毒理学研究 老鼠和猪。为了完成II期申请，我们将准备并提交IND，以便开始 CTX-002治疗ARDS的首次人体临床试验。

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.