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.

项目概要/摘要在美国，有 2000 万人酗酒，每年有 180 万名酗酒者入院治疗。酒精性肺综合征被认为是这一人群发病和死亡的重要原因。人口，估计死亡人数接近酒精引起的肝硬化。肺部持续而深刻的氧化应激，导致酒精介导的肺损伤，定义为功能失调的上皮屏障和对急性损伤的过度炎症反应。容易患上急性呼吸窘迫综合征 (ARDS)，这是一种严重的肺水肿，通常会导致酗酒者更容易受到肺炎、创伤和呼吸衰竭等伤害。脓毒症，酒精性肺容易产生这种病理性高炎症反应。在这种情况下，没有可用于治疗酒精肺综合征并保留肺功能的疗法最近的研究表明，针对酒精肺中的紧密连接是一种有前途的方法。预防重症患者上皮屏障完整性丧失和急性呼吸衰竭的治疗方法 FirstString Research 开发了一种名为 aCT1 的新型肽，可以稳定酒精患者的紧张状态。 aCT1 是一种肽模拟物，可增强细胞间屏障并预防病理性炎症。间隙连接蛋白 Connexin43 (Cx43) C 末端结合 ZO-1，改变与其连接的相互作用 aCT1 肽可稳定细胞膜上的 ZO-1，防止紧密连接降解。 FirstString Research 目前已开发出 Granexin® 来应对损伤和加强上皮屏障。凝胶，一种 aCT1 肽的局部制剂，通过了三项 2 期临床试验，用于减少疤痕和这些临床结果反复证明了aCT1的稳定能力。上皮屏障并促进上皮对损伤的有效反应，这是酒精肺的病理核心初步数据表明 aCT1 能够保护肺上皮屏障功能和提高体内直接肺部损伤的生存率在这一阶段的 SBIR 中，我们建议确定。我们相信 aCT1 作为治疗酒精性肺综合征的功效。酒精损伤的肺中的连接点将稳定肺上皮屏障，减轻病理免疫反应，并预防急性呼吸衰竭的发展，以提高酒精患者的生存率。靶向细胞间连接代表了一种稳定气液屏障和保护肺的新方法在酒精性肺综合征的临床相关二次打击模型中，我们将测试其在酒精性肺综合征中的功能。 aCT1治疗后损伤后保持上皮屏障完整性并提高体内存活率的能力。将利用从酒精患者身上分离出的初级气道肺上皮细胞来测试 aCT1 在恢复酒精中的功效人肺的屏障功能，进一步证明 aCT1 是治疗酒精性肺的可行疗法综合征并支持该疗法在 II 期 SBIR 中的进一步开发。