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入院的10％，死亡率为高达46％。在19009年大流行期间，ARDS的发生率急剧上升。尽管有所改善在重症监护和早期发现肺损伤的过程中，ARDS的管理仍然很大程度上支持。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诱导的肺损伤（VILI）可以施加第二次侮辱，使结果恶化。一系列侮辱，包括创伤，败血症，肺部感染或毒素暴露在于急性肺损伤（ALI）和随后的系统性炎症反应和对ARDS的发展，导致肺合顺顺和肺纤维化的改变。 ARDS的主要致病特征是持续激活炎症和氧化应激。在ALI之后，肺巨噬细胞产生促炎性细胞因子，导致募集其他炎症细胞和活性氧（ROS）的产生。炎症和氧化应激的持续扩增会导致进展到ards，促进长期纤维化和发病率。 Ceria Therapeutics正在开发一种新型的治疗产品CTX-002，它协同靶向两者炎症和氧化应激。 CTX-002（CNP-MIR146A）是氧化葡萄纳米粒子（CNP）具有ROS清除特性，与抗炎的miR146a模拟物相结合以靶向两个ROS 和炎症反应。在I阶段应用程序的支持下，我们证明了一个 CTX-002的给药可以防止博来霉素，MRSA和脂多糖诱导的炎症和肺部受伤，即使受伤三到七天。此外，用CTX-002处理结果在改善肺力学和预防随后的VILI中。我们还证明了系统性静脉注射单剂量和重复剂量最多10倍CTX-002的临床剂量显示没有大鼠毒性的迹象。该阶段II提案的目标是1）确定肺部分布猪中的CTX-002证明了药物的气管内给药导致全身暴露 CTX-002但肺部浓度增加； 2）扩大合成和完整的分析 CTX-002的表征，配方和稳定性； 3）进行符合GLP的安全性和毒理学研究在大鼠和猪中。要完成此II阶段申请，我们将准备并提交一个IND以开始清关 CTX-002对ARDS的首次人类临床试验。