Inducible HMGB1 antagonist for viral-induced acute lung injury.

诱导型 HMGB1 拮抗剂，用于治疗病毒引起的急性肺损伤。

• 批准号: 10591804
• 负责人: JORGE C BLANCO
• 金额: $ 48.81万
• 依托单位: SIGMOVIR BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591804
• 关键词: 2019-nCoV; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Adenovirus Vector; Adenoviruses; Agonist; Animal Model; Bacterial Infections; Biological Markers; COVID-19 cytokine storm; COVID-19 pandemic; Cells; Cessation of life; Cotton Rats; Data; Dengue Virus; Development; Dimerization; Disease; Disease Progression; Ebola virus; Engineering; Experimental Animal Model; Family; Gene Expression; Goals; HMGB1 gene; Homeostasis; Hospitalization; Human; Immune response; Infectious Agent; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Influenza; Injury; Innate Immune Response; Intervention; Life; Ligands; Lipopolysaccharides; Lung; Mediating; Mediator; Molecular; Multiple Organ Failure; Mus; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Phase; Predisposition; Process; Production; Publishing; Pulmonary Inflammation; Reporting; Research; Resolution; Respiratory Disease; Respiratory Tract Infections; Rodent Model; SARS-CoV-2 exposure; SARS-CoV-2 infection; Sepsis; Severity of illness; Sigmodon; Signal Pathway; Signal Transduction; Small Business Technology Transfer Research; Sterility; Structure; Symptoms; System; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toll-like receptors; Treatment Efficacy; Viral; Virus; Work; antagonist; cell injury; chemokine; clinically relevant; cytokine; cytokine release syndrome; efficacy testing; human disease; human pathogen; inflammatory lung disease; influenza infection; influenza virus strain; inhibitor; innovation; insight; microorganism interaction; mouse model; novel; novel strategies; pathogen; pre-clinical; prototype; receptor; respiratory virus; response; small molecule; therapeutic development; therapeutic target; therapeutically effective; tool; translational therapeutics

For more than a decade, our work has focused on development of therapeutic interventions for viral- and bacterial-induced acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS). Significantly, we identified the Toll-like receptor 4 (TLR4) signaling pathway as key to the host response to influenza and secondary bacterial infection following influenza. We also identified High Mobility Group Box 1 (HMGB1), a host-derived “danger-associated molecular pattern” (DAMP), as a biomarker of disease severity for multiple respiratory viruses and detected greatly elevated levels in sera from patients hospitalized for severe influenza and SARS-CoV-2 infections. Importantly, our data indicate that HMGB1 is a central mediator of influenza-induced respiratory disease that acts by stimulating TLR4/MD-2 to elicit the potent inflammatory response associated with ALI/ARDS. Therapeutic administration of TLR4 antagonists (e.g., Eritoran and many others), as well as small molecule HMGB1 antagonists, mitigate the life-threatening pulmonary manifestations of acute lung injury (ALI) and lethality in preclinical rodent models. The identification of these promising therapeutic targets has led us to the central hypothesis that our findings may well be applicable to other ALI- inducing agents. Indeed, since our earliest reports of the efficacy of the TLR4 antagonist, Eritoran, in influenza- induced disease in both mice and cotton rats (Sigmodon hispidus, a species uniquely susceptible to non-adapted human viruses), this agent has been reported to blunt disease in animal models of Ebola virus and Dengue virus, leading to a reduction in cytokine and chemokine production and reduced disease symptoms. Given the clinical relevance of ALI and ARDS that has been exposed by the SARS-CoV-2 pandemic, and the striking similarities between influenza- and SARS-Cov-2-induced ALI/ARDS caused by a cytokine storm leading to loss of homeostasis and, ultimately, multiorgan failure and death, we propose, as the central goal of this phase I STTR, to evaluate the therapeutic efficacy of our newly developed, inflammation-inducible, adenoviral vector encoding the HMGB1 antagonist, “HMGB1 Box A,” to ameliorate severe influenza-induced inflammation. We will test the efficacy of our intervention in murine models of LPS-induced lung inflammation and mouse-adapted influenza infection, and in cotton rats challenged with non-adapted human influenza strains for which we have correlated HMGB1 levels with disease severity. We predict that our innovative strategy will provide a novel approach to treatment of inflammatory lung disease that is mediated by multiple non-infectious and infectious agents that cause ALI/ARDS.

十多年来，我们的工作重点是开发针对病毒的治疗干预措施-以及 细菌性急性肺损伤(ALI)和更严重的急性呼吸窘迫综合征(ARDS)。 值得注意的是，我们发现Toll样受体4(TLR4)信号通路是宿主对 流感和流感后的继发性细菌感染。我们还确定了高移动性组框1 (HMGB1)，一个宿主衍生的“危险相关分子模式”(DAMP)，作为疾病严重程度的生物标志物 多种呼吸道病毒，并在重症住院患者的血清中检测到显著升高的水平 流感和SARS-CoV-2感染。重要的是，我们的数据表明HMGB1是 流感引起的呼吸系统疾病，通过刺激TLR4/MD-2诱导强大的炎症性 与ALI/ARDS相关的响应。TLR4拮抗剂的治疗性给药(例如厄立特里亚和许多 其他)，以及小分子HMGB1拮抗剂，减轻危及生命的肺部表现 临床前啮齿动物模型中急性肺损伤(ALI)和致死率的关系。确定了这些有希望的人 治疗靶点使我们得出了一个中心假设，即我们的发现很可能适用于其他ALI- 诱导剂。事实上，自从我们最早报道TLR4拮抗剂厄立特里亚对流感的疗效以来， 在小鼠和棉鼠(Sigmodon Hispidus)中诱发的疾病，这是一种唯一对不适应 人类病毒)，这种药物已被报道在埃博拉病毒和登革热病毒的动物模型中钝化疾病， 导致细胞因子和趋化因子的产生减少，疾病症状减轻。考虑到临床上 SARS-CoV-2大流行暴露出的ALI和ARDS的相关性及其惊人的相似性 流感病毒和SARS-CoV-2诱导的细胞因子风暴导致的ALI/ARDS之间的关系 动态平衡，最终，多器官衰竭和死亡，我们建议，作为这一阶段STTR的中心目标， 评价我们新开发的可诱导炎症的重组腺病毒载体的治疗效果 HMGB1拮抗剂“HMGB1 Box A”，用于缓解严重流感引起的炎症。我们将测试 我们对脂多糖诱导的小鼠肺部炎症和小鼠适应流感模型的干预效果 感染，以及用我们已经关联的未适应的人类流感毒株挑战的棉花大鼠 HMGB1水平与病情严重程度相关。我们预测，我们的创新战略将提供一种新的方法 由多种非感染性和感染性介质介导的炎症性肺部疾病的治疗 因为ALI/ARDS。