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.

项目总结-急性呼吸窘迫综合征（ARDS）占ICU住院患者的10%