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

• 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
• 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

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% 死亡率高达46%。去年，由于这部小说，这种发病率急剧上升。 引起新冠肺炎的冠状病毒(SARS-CoV-2)，而急性呼吸窘迫综合征是新冠肺炎患者的主要死亡原因。 在美国，新冠肺炎已经感染了3000多万人，导致55万人死亡。尽管 在重症监护和肺损伤早期发现方面的改进，ARDS的管理在很大程度上仍然 支持性的，虽然机械通风可以提供必要的生命支持，但受损的肺 机械和随后的呼吸机诱导的肺损伤(VILI)可以施加第二次侮辱，使情况恶化 结果。一系列全身炎性侮辱，包括创伤、脓毒症、新冠肺炎或来自 中毒暴露与急性肺损伤(ALI)和ARDS的发展有关，并导致改变 在肺顺应性和肺纤维化方面。虽然ALI的病因是多因素的，但一个主要的致病特征是 持续激活炎症和氧化应激。ALI后，肺巨噬细胞产生促凝素 炎性细胞因子，导致额外的炎性细胞的招募和产生 活性氧(ROS)。这种促炎状态由关键的促炎细胞因子调节，如 即白介素6(IL-6)和白介素8(IL-8)，由促炎转录因子NFkB刺激。一个 炎症的另一层控制是通过miR-146a，一种调节的microRNA，作为一种 抑制NFkB活化及其下游IL-6和IL-8对炎症的分子刹车作用 表情。CeO2治疗公司开发了一种新的策略，以协同作用针对炎症和 氧化应激。设计并合成了一种新型的氧化铈纳米颗粒。 ROS清除性能，结合抗炎miR-146a模拟物(CNP-miR146a)，靶向 ROS和炎症反应。在博莱霉素诱导的ALI模型中令人信服的初步数据中， 研究发现，在损伤时一次性给予CNP-miR146a可以预防炎症和 纤维化和改善肺力学的结果。然而，抢救肺损伤的能力和 损伤发生后的肺力学改善情况尚待确定。基于我们的假设 CNP-miR146a通过减少炎症和氧化应激，减少纤维化，从而改善ALI 肺力学，这项建议的目的是证明我们的疗效特别是 CNP-miR146a气管内给药制剂(CTX-002)抢救二期ALI 临床相关的ALI动物模型并开展试点安全评估。CTX-002的疗效观察 将在VILI诱导的ALI模型(特定目标1)和II)活体细菌感染的两次打击模型中进行评估 (金黄色葡萄球菌)，然后是VILI(具体目标2)。特定目标3急性7天耐受性和毒代动力学研究 将以大鼠为试点进行安全性评估。