Evaluation of a Novel Therapeutic Approach to Treat Alcoholic Lung Syndrome

治疗酒精性肺综合征的新治疗方法的评价

基本信息

批准号：
10081623
负责人：
Carissa James
金额：
$ 25.21万
依托单位：
XEQUEL BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081623
关键词：
Actins Acute Acute respiratory failure Adult Respiratory Distress Syndrome Air Alcohol abuse Alcohols Alveolar Alveolar Cell Bacterial Pneumonia Binding Cell membrane Cells Cessation of life Chronic Chronic lung disease Cicatrix Clinical Connexin 43 Connexins Critical Illness Cytoskeleton Data Development Endotoxemia Epithelial Epithelial Cells Epithelium Evaluation Exposure to Floods Formulation Functional disorder Gases Gel Homeostasis Hospitalization Human Immune response Impaired wound healing Impairment Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Injury Intercellular Junctions Liquid substance Liver Cirrhosis Lung Lung diseases Maintenance Mediating Membrane Modeling Morbidity - disease rate Organ Oxidative Stress Pathologic Pathology Patients Peptides Phase Phase II Clinical Trials Pneumonia Population Proteins Pulmonary Edema Rattus Research Respiratory Failure Respiratory physiology Scaffolding Protein Secondary to Sepsis Site Small Business Innovation Research Grant Syndrome Testing Therapeutic Tight Junctions Time Tissues Trauma United States Up-Regulation Vulnerable Populations aerosolized alcohol exposure alveolar epithelium chronic alcohol ingestion chronic wound clinically relevant cytokine immune function improved in vivo innovation lung injury lung preservation mortality mouse model novel novel strategies novel therapeutic intervention novel therapeutics peptidomimetics preservation prevent problem drinker pulmonary function repaired response response to injury restoration seal therapeutic target therapy development zonula occludens-1 protein

项目摘要

PROJECT SUMMARY/ABSTRACT Twenty million people abuse alcohol in the United States and 1.8 million alcoholics are hospitalized every year. Alcoholic lung syndrome is recognized as a significant cause of morbidity and mortality amongst this large population, with estimated deaths approaching that of alcohol induced liver cirrhosis. Alcohol abuse induces persistent and profound oxidative stress in the lung, causing an alcohol mediated lung injury defined by dysfunctional epithelial barriers and an exaggerated inflammatory response to acute insults. The alcoholic lung is primed to develop acute respiratory distress syndrome (ARDS), a severe form of pulmonary edema that often precedes respiratory failure. Alcoholics are more susceptible to the insults including pneumonia, trauma, and sepsis, against which the alcoholic lung is predisposed to mount this pathologic hyperinflammatory response. There are no therapies available to treat alcoholic lung syndrome and preserve pulmonary function in this vulnerable population. Recent research suggests that targeting tight junctions in the alcoholic lung is a promising therapeutic approach to preventing loss of epithelial barrier integrity and acute respiratory failure in critically ill alcoholic patients. FirstString Research has developed a novel peptide, termed aCT1, that stabilizes tight junctions, strengthens intercellular barriers, and prevents pathological inflammation. aCT1 is a peptide mimetic of the gap junction protein Connexin43 (Cx43) C-terminus that binds ZO-1, altering interactions with its junctional binding partners. aCT1 peptide stabilizes ZO-1 at the cell membrane, preventing tight junction degradation in response to injury and strengthening epithelial barriers. FirstString Research has currently advanced Granexin® gel, a topical formulation of aCT1 peptide, through three Phase 2 clinical trials for scar reduction and the treatment of chronic wounds. These clinical results have repeatedly demonstrated the ability of aCT1 to stabilize epithelial barriers and promote an effective epithelial response to injury, pathologies core to alcoholic lung syndrome. Preliminary data demonstrate the ability of aCT1 to preserve lung epithelial barrier function and improve survival in response to direct pulmonary insult in vivo. In this Phase I SBIR, we propose to determine the efficacy of aCT1 as a treatment for alcoholic lung syndrome. We believe therapeutically targeting tight junctions in the alcohol damaged lung will stabilize lung epithelial barriers, mitigate the pathological immune response, and prevent development of acute respiratory failure to improve survival of alcoholic patients. Direct targeting of intercellular junctions represents a novel approach to stabilize the air-liquid barrier and preserve lung function in alcoholic lung syndrome. In clinically relevant two-hit models of alcoholic lung syndrome, we will test the ability of aCT1 treatment post insult to preserve epithelial barrier integrity and improve survival in vivo. We will utilize primary airway lung epithelial cells isolated from alcoholic patients to test aCT1 efficacy in restoring barrier function in the human lung, providing further evidence that aCT1 is a viable therapeutic for alcoholic lung syndrome and supporting the further development of this therapy in a Phase II SBIR.

项目摘要/摘要每年在美国滥用酒精和180万酗酒者。酒精性肺综合征被认为是造成发病率和死亡率的重要原因人口，估计的死亡接近酒精诱导的肝硬化。酗酒引起肺部持续而深刻的氧化应激，导致酒精介导的肺损伤功能失调的上皮障碍和对急性侮辱的炎症反应。酒精肺被启发出来发展急性呼吸窘迫综合征（ARDS），这是一种严重的肺水肿形式先于呼吸衰竭。酗酒者更容易受到包括肺炎，创伤和败血症，含含酒精的肺会易于安装这种病理性高炎症反应。没有可用于治疗酒精肺综合征并保留肺功能的疗法脆弱的人口。最近的研究表明，靶向酒精肺紧密连接是一个承诺预防危重患病的上皮屏障完整性和急性呼吸衰竭的治疗方法酒精患者。第一串研究开发了一种称为ACT1的新型肽，可稳定紧密连接，优势细胞间屏障并防止病理炎症。 ACT1是一个辣椒模仿 GAP连接蛋白连接蛋白连接（CX43）C末端结合ZO-1，改变了与其连接的相互作用约束伙伴。 ACT1肽稳定在细胞膜处的ZO-1，防止连接紧密降解对伤害和加强上皮屏障的反应。 FirstString Research目前已提前Granexin® 凝胶是ACT1肽的局部配方，通过三阶段2临床试验的疤痕减少和治疗慢性伤口。这些临床结果反复证明了ACT1稳定的能力上皮屏障并促进对损伤的有效上皮反应，病理核心对酒精肺综合征。初步数据证明了ACT1保持肺上皮屏障功能的能力和改善对直接肺部损伤体内的生存率。在此阶段I SBIR中，我们建议确定 ACT1作为酒精肺综合征的治疗效率。我们认为热靶向紧密酒精中肺部损坏的连接处将稳定肺上皮屏障，减轻病理免疫反应，并防止发展急性呼吸衰竭以改善酒精患者的存活率。直接的靶向细胞间连接代表了一种稳定空气屏障并保存肺的新方法酒精肺综合征的功能。在临床上相关的酒精肺综合征的两次冲击模型中，我们将测试 ACT1治疗后的侮辱性能力保留上皮屏障完整性并改善体内生存。我们将利用从酒精患者中分离出的原发气道肺上皮细胞来测试ACT1效率人肺中的障碍功能，提供了进一步的证据，表明ACT1是酒精肺的可行疗法综合征并支持II期SBIR中这种疗法的进一步发展。