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：
10758905
负责人：
David Jackson
金额：
$ 80.74万
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 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10758905
关键词：
Abdomen Acute Lung Injury Acute Respiratory Distress Syndrome Admission activity Adverse effects Anti-Inflammatory Agents Award Biological Assay Bleomycin COVID-19 pandemic Cells Cerium Cessation of life Chemical Exposure Chemistry Clinical Clinical Trials Collaborations Critical Care Cyclophosphamide Development Dose Drug Kinetics Early Diagnosis Etiology Failure Family suidae Feedback Fibrosis Formulation Gases Generations Goals Hospital Mortality Hour IL8 gene Impairment Incidence Inductively Coupled Plasma Mass Spectrometry Inflammation Inflammatory Inflammatory Response Inhalation Injury Interleukin-6 Intravenous Laboratories Life Lipopolysaccharides Lung Lung Compliance Lung infections Macrophage Maximum Tolerated Dose Measures Mechanical ventilation Mechanics MicroRNAs Miniature Swine Modeling Molecular Morbidity - disease rate Mustard Gas National Heart, Lung, and Blood Institute Nuclear Operative Surgical Procedures Organ Outcome Oxidative Stress Particle Size Pathogenesis Pathogenicity Patients Pharmaceutical Preparations Pharmacological Treatment Phase Pilot Projects Poison Preparation Prevention Process Production Property Pulmonary Fibrosis Rattus Reactive Oxygen Species Recommendation Recovery Research Respiratory System Rodent Safety Sepsis Small Business Innovation Research Grant Therapeutic Tissues Toxic effect Toxicology Toxin Trauma Ventilator-induced lung injury cerium oxide nanoparticle comparison control cytokine first-in-human improved intravenous administration lung injury manufacture methicillin resistant Staphylococcus aureus mimetics mortality novel novel therapeutics phase 2 study pre-Investigational New Drug meeting prevent pulmonary function recruit scale up side effect supplemental oxygen systemic inflammatory response

项目摘要

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.

概括急性呼吸窘迫综合征 (ARDS) 占全球 ICU 入院人数的 10%，死亡率很高高达46%。在 COVID-19 大流行期间，ARDS 发病率急剧上升。尽管有所改进在重症监护和肺损伤的早期发现方面，ARDS 的治疗在很大程度上仍然是支持性的。虽然机械通气可以提供必要的生命支持、受损的肺力学和随后的呼吸机引起的肺损伤（VILI）可能会造成二次损伤，导致结果恶化。一系列的辱骂，包括创伤、脓毒症、肺部感染或毒素暴露，与急性肺损伤 (ALI) 和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。 ARDS 的一个主要致病特征是持续激活炎症和氧化应激。 ALI 后，肺巨噬细胞产生促炎细胞因子，导致额外炎症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 ARDS 的进展，促进长期纤维化和发病。 Ceria Therapeutics 正在开发一种新型治疗产品 CTX-002，该产品可协同作用于炎症和氧化应激。 CTX-002 (CNP-miR146a) 是一种氧化铈纳米颗粒 (CNP)，具有 ROS 清除特性，与抗炎 miR146a 模拟物结合以靶向两种 ROS 和炎症反应。在第一阶段应用程序的支持下，我们已经证明了单个给予 CTX-002 可以预防博来霉素、MRSA 和脂多糖诱导的炎症和肺部损伤，即使是在受伤后三到七天给药。此外，CTX-002治疗导致改善肺力学并预防随后的 VILI。我们还证明了系统性静脉单次和重复剂量给药高达 CTX-002 预期临床剂量的 10 倍对大鼠没有毒性迹象。该第二阶段提案的目标是 1) 确定肺部分布在猪身上进行 CTX-002 试验，证明气管内给药不会导致药物的全身暴露 CTX-002但肺部浓度增加； 2) 放大合成和完整分析 CTX-002 的表征、配方和稳定性； 3) 进行符合GLP标准的安全性和毒理学研究在大鼠和猪中。为了完成第二阶段申请，我们将准备并提交 IND 以便开始审批 CTX-002 治疗 ARDS 的首次人体临床试验。