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

急性呼吸窘迫综合征（ARDS）占ICU入院人数的10% 死亡率高达46%。这种发病率在去年急剧上升， 急性呼吸窘迫综合征（ARDS）是引起COVID-19的冠状病毒（SARS-CoV-2）的主要病原体，而ARDS是COVID-19患者死亡的主要原因。 在美国，COVID-19已经感染了超过3000万人，并导致55万人死亡。尽管 随着重症监护和肺损伤早期检测的改善，ARDS的管理在很大程度上仍然是 支持性，虽然机械通气可以提供必要的生命支持，但受损的肺功能 机械和随后的呼吸机诱导的肺损伤（VILI）可能会造成第二次损伤， 结果。一系列全身性炎症损伤，包括创伤、败血症、COVID-19或局部损伤， 毒性暴露与急性肺损伤（ALI）和ARDS的发展有关， 肺顺应性和肺纤维化。虽然ALI的病因是多因素的，但一个重要的致病特征是： 炎症和氧化应激的持续激活。在ALI后，肺巨噬细胞产生前- 炎症细胞因子导致额外的炎症细胞的募集和炎症细胞因子的产生。 活性氧（ROS）。这种促炎状态由关键的促炎细胞因子调节， 如白细胞介素-6（IL-6）和IL-8，其由促炎转录因子NF κ B刺激。一个 炎症的另一个控制层是通过miR-146 a，一种调节性microRNA， 通过抑制NFkB活化和下游IL-6和IL-8对炎症的“分子制动” 表情Ceria Therapeutics开发了一种新的策略，以协同靶向炎症和炎症。 氧化应激已经设计和合成了新型氧化铈纳米颗粒（CNP），其具有 与抗炎miR-146 a模拟物（CNP-miR 146 a）缀合的ROS清除特性， ROS和炎症反应。在博来霉素诱导的ALI模型中令人信服的初步数据中， 发现在损伤时一次性施用CNP-miR 146 a预防炎症， 纤维化并导致改善的肺力学。然而，抢救肺损伤的能力和 损伤发生后改善肺力学仍有待确定。基于我们的假设， CNP-miR 146 a将通过减少炎症和氧化应激、减少纤维化来拯救ALI，从而改善ALI的发生。 肺力学，这项建议的目的是证明我们的疗效，特别是 用于肺内递送的CNP-miR 146 a的配制形式（CTX-002），以在两个受试者中挽救现有的ALI。 临床相关的ALI动物模型，并进行初步安全性评估。CTX-002的疗效 i）将在VILI诱导的ALI模型（特异性目标1）和ii）活细菌感染的两次打击模型中评价 （S.金黄色葡萄球菌），然后是VILI（特异性目标2）。在特定目标3中，一项急性7天耐受性和毒代动力学研究 将在大鼠中作为试点进行安全性评估。

PROJECT SUMMARY - Acute respiratory distress syndrome (ARDS) accounts for 10% of ICU admissions worldwide with a mortality as high as 46%. This incidence has risen dramatically in the last year due to the novel coronavirus (SARS-CoV-2) causing COVID-19, and ARDS is the leading cause of death in COVID-19 patients. In the United States, COVID-19 has infected over 30 million and killed 550,000 people already. Despite improvements in critical care and early detection of lung injury, the management of ARDS remains largely supportive, and while 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 systemic inflammatory insults, including trauma, sepsis, COVID-19, or local injury from toxic exposure, are associated with acute lung injury (ALI) and the development of ARDS, and result in alterations in lung compliance and lung fibrosis. While the etiology of ALI is multifactorial, a central pathogenic feature is a 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). This pro-inflammatory state is regulated by key pro-inflammatory cytokines such as interleukin-6 (IL-6) and IL-8 which are stimulated by NFkB, a pro-inflammatory transcription factor. An additional layer of control of inflammation is through miR-146a, a regulatory microRNA that serves as a “molecular brake” on inflammation through inhibition of NFkB activation and downstream IL-6 and IL-8 expression. Ceria Therapeutics has developed a novel strategy to synergistically target both inflammation and oxidative stress. Novel cerium oxide nanoparticles (CNPs) have been designed and synthesized that possess ROS scavenging properties, conjugated with an anti-inflammatory miR-146a mimetic (CNP-miR146a), to target both ROS and the inflammatory response. In compelling preliminary data in a bleomycin-induced model of ALI, It was found that one-time administration of CNP-miR146a at the time of injury prevents inflammation and fibrosis and results in improved pulmonary mechanics. However, the ability to rescue lung injury and improve pulmonary mechanics after injury has occurred remain to be determined. Based on our hypothesis that CNP-miR146a will rescue ALI by reducing inflammation and oxidative stress, decrease fibrosis, and thus improve pulmonary mechanics, the objective of this proposal is to demonstrate the efficacy of our especially formulated form of CNP-miR146a for intratracheal delivery (CTX-002) to rescue existing ALI in two clinically relevant ALI animal models and to carry out a pilot safety assessment. The efficacy of CTX-002 in i) will be evaluated in a VILI-induced ALI model (Specific Aim 1) and ii) a two-hit model of live bacterial infection (S. aureus) followed by VILI (Specific Aim 2). In Specific Aim 3 an acute 7-day tolerability and toxicokinetic study in rats as a pilot safety assessment will be carried out.