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

利用 CNP-miR146a 靶向炎症和氧化应激治疗急性肺损伤

基本信息

批准号：
10382076
负责人：
David Jackson
金额：
$ 29.93万
依托单位：
CERIA THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382076
关键词：
2019-nCoV Abdomen Acute Acute Lung Injury Acute Respiratory Distress Syndrome Admission activity Alveolar Macrophages Animal Model Anti-Inflammatory Agents Bacteria Bacterial Infections Bleomycin Body Weight COVID-19 COVID-19 mortality COVID-19 pandemic COVID-19 patient COVID-19/ARDS Cause of Death Cells Cessation of life Clinical Pathology Critical Care Cyclophosphamide Data Development Dose Early Diagnosis Etiology Failure Fibrosis Generations Goals Hospital Mortality Hour IL8 gene Impairment Incidence Inflammation Inflammatory Inflammatory Response Inhibition of NF-KB activation Injury Interleukin-6 Intravenous Lead Life Lung Lung Compliance Measures Mechanical ventilation Mechanics Methods MicroRNAs Modeling Molecular Morbidity - disease rate Mus NF-kappa B Operative Surgical Procedures Outcome Oxidative Stress Pathogenesis Pathogenicity Patients Persons Pharmacological Treatment Phase Phenotype Production Property Pulmonary Fibrosis Pulmonary Inflammation Rattus Reactive Oxygen Species Research Rodent Safety Schedule Secure Sepsis Small Business Innovation Research Grant Staphylococcus aureus Therapeutic Time Toxic effect Toxicant exposure Toxicokinetics Toxicology Trauma Tube United States Ventilator Ventilator-induced lung injury Virus Diseases base cGMP production cerium oxide nanoparticle clinically relevant cytokine design efficacy validation endotracheal first-in-human improved lung injury macrophage mimetics morphometry mortality mouse model novel novel coronavirus novel strategies preclinical efficacy prevent pulmonary function recruit safety assessment safety study systemic toxicity transcription factor

项目摘要

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.

项目摘要 - 急性呼吸窘迫综合征 (ARDS) 占 ICU 入院人数的 10% 由于这部小说，去年这种病死率在全球范围内急剧上升。冠状病毒 (SARS-CoV-2) 引起 COVID-19，ARDS 是 COVID-19 患者死亡的主要原因。在美国，COVID-19 已感染超过 3000 万人，并导致 55 万人死亡。尽管重症监护和肺损伤的早期发现有所改善，但 ARDS 的治疗仍然在很大程度上支持性，虽然机械通气可以提供必要的生命支持，但受损的肺力学和随后的呼吸机引起的肺损伤（VILI）可能会造成第二次损伤，并使情况恶化一系列全身炎症损伤，包括创伤、脓毒症、COVID-19 或局部损伤。有毒物质暴露，与急性肺损伤 (ALI) 和 ARDS 的发展相关，并导致改变肺顺应性和肺纤维化虽然 ALI 的病因是多因素的，但一个主要的致病特征是 ALI 后，炎症和氧化应激持续激活，肺巨噬细胞产生促炎症反应。炎症细胞因子导致额外炎症细胞的募集并产生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，它们受到促炎转录因子 NFkB 的刺激。炎症的额外控制层是通过 miR-146a 实现的，这是一种调节性 microRNA，可充当通过抑制 NFkB 激活和下游 IL-6 和 IL-8 对炎症进行“分子刹车” Ceria Therapeutics 开发了一种协同靶向炎症和表达的新策略。已设计并合成了具有氧化应激作用的新型氧化铈纳米颗粒（CNP）。 ROS 清除特性，与抗炎 miR-146a 模拟物 (CNP-miR146a) 结合，以靶向博来霉素诱导的 ALI 模型中的 ROS 和炎症反应令人信服。研究发现，在损伤时一次性给予 CNP-miR146a 可预防炎症和纤维化并改善肺力学，但拯救肺损伤的能力和能力。根据我们的假设，受伤后肺力学的改善仍有待确定。 CNP-miR146a 将通过减少炎症和氧化应激来拯救 ALI，减少纤维化，从而改善肺力学，该提案的目的是证明我们特别的功效用于气管内递送的 CNP-miR146a 配方 (CTX-002) 可挽救两例患者中现有的 ALI 临床相关的 ALI 动物模型并进行了试点安全性评估 CTX-002 的功效。 i) 将在 VILI 诱导的 ALI 模型（具体目标 1）和 ii) 活细菌感染的两次打击模型中进行评估（金黄色葡萄球菌），然后进行 VILI（具体目标 2），在具体目标 3 中进行急性 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评估。