Novel Therapeutic Approach for Sepsis: Blocking the Vascular Response to Cytokine

败血症的新治疗方法：阻断血管对细胞因子的反应

基本信息

批准号：
8215618
负责人：
ALAN L MUELLER
金额：
$ 27.42万
依托单位：
NAVIGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215618
关键词：
ADP-ribosylation factor 6 Affect Animal Model Antibiotic Therapy Antibiotics Award Blood Vessels Blood flow Cessation of life Clinical Coagulation Process Collaborations Complex Cytokine Network Pathway Development Dose Endothelial Cells Functional disorder Funding Goals Hour Immigration In Vitro Infectious Agent Inflammatory Injury Interleukins Laboratories Ligands Ligation Metabolic Modeling Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Operative Surgical Procedures Organ Pathway interactions Patients Permeability Phenotype Pneumonia Proteins Pseudomonas Pseudomonas aeruginosa Puncture procedure Research Sepsis Signal Transduction Syndrome Testing Thrombin Time Trauma Tumor Necrosis Factor-alpha United States Vascular Endothelial Growth Factors Work commercialization cytokine effective therapy efficacy testing hemodynamics human TNF protein in vivo inhibitor/antagonist mortality mouse model novel novel therapeutic intervention prevent public health relevance receptor response small molecule therapeutic protein

项目摘要

DESCRIPTION (provided by applicant): In the United States alone, sepsis affects approximately 700,000 patients and leads to death of over 210,000 people per year. Sepsis is a clinical syndrome that results from a complex interaction between host and infectious agents, and is characterized by systemic activation of inflammatory and coagulation cascades. Hemodynamic changes, widespread microcirculatory disturbances and cellular alterations, leading to an uncoupling between blood flow and metabolic requirements, are implicated in the development of multiple organ dysfunction, responsible for most of deaths. Navigen believes that it has a unique means of preventing the hemodynamic changes and microcirculatory disturbances - the vascular leak - associated with sepsis. Our scientific co-founder, Dr. Dean Li, identified a novel receptor, Robo4, that is expressed in mature vessels and is upregulated following endothelial injury. Robo4, when activated by its protein ligand, Slit2, reduces vascular leak in vitro and in vivo. Our work has further illustrated that activation of the Robo4 receptor interferes with the downstream signaling cascades from multiple permeability factors including TNF-alpha, interleukins, and thrombin. We have cloned an active fragment of Slit2, Slit2N, which appears to have identical efficacy to Slit2, and is more easily produced than the native protein. Navigen has demonstrated that Slit2N is effective in reducing mortality in the animal model of sepsis induced by cecal ligation and puncture. Due to the challenges associated with protein therapeutics, Dr. Li sought to identify a small molecule that could affect the Robo4 pathway in a manner similar to Slit2N. Dr. Li and collaborators determined that a critical downstream step in Robo4 activation is the inhibition of a small GTPase, ADP ribosylation factor 6 (ARF6). Dr. Li and colleagues further determined that ARF6 can be blocked through inhibition of its ARF-GEF, cytohesin2/ARNO, using a small molecule inhibitor, NAV838. Dr. Li's laboratory, in collaboration with Navigen, has shown that inhibition of ARF6, either by blocking its ARF-GEF or through the inhibitory activation of Robo4 by Slit2N, produced similar phenotypes: inhibition of VEGF-induced migration in endothelial cells. Navigen is seeking funding under this application to confirm the efficacy of Slit2N in the treatment of sepsis and to determine whether NAV838, as a small molecule, may be an even more viable approach to treating sepsis than Slit2N. Navigen would anticipate advancing the superior compound forward to IND for eventual commercialization. The proposed research is intended to accomplish 3 goals: 1) develop animal models of sepsis induced by pseudomonas pneumonia (PAP) in which antibiotic therapy dose and timing are titrated to achieve seven-day mortality of approximately 50%, 2) test efficacy and indentify most efficacious dose of Slit2N combined with antibiotic therapy in models of CLP and PAP (PAP established in Aim 1), 3) determine whether NAV838 combined with antibiotics may have greater efficacy than Slit2N plus antibiotics by testing in animal models of CLP and PAP. PUBLIC HEALTH RELEVANCE: Sepsis is a clinical syndrome that results from a complex interaction between host and infectious agents, and is characterized by systemic activation of multiple inflammatory pathways, including cytokine network and coagulation. Mortality associated with severe sepsis ranges between 30 to 50 percent and sepsis is the leading cause of morbidity and mortality in surgical patients and trauma victims. Currently, there are no effective therapies for the treatment of Sepsis.

描述（由申请人提供）：仅在美国，脓毒症每年影响约 700,000 名患者，并导致超过 210,000 人死亡。脓毒症是一种临床综合征，由宿主和传染原之间复杂的相互作用引起，其特征是炎症和凝血级联的全身激活。血流动力学变化、广泛的微循环障碍和细胞改变，导致血流和代谢需求之间的脱钩，与多器官功能障碍的发展有关，而多器官功能障碍是大多数死亡的原因。 Navigen 认为，它具有预防与脓毒症相关的血流动力学变化和微循环障碍（血管渗漏）的独特方法。我们的科学联合创始人 Dean Li 博士发现了一种新型受体 Robo4，它在成熟血管中表达，并在内皮损伤后表达上调。 Robo4 被其蛋白质配体 Slit2 激活后，可减少体外和体内的血管渗漏。我们的工作进一步表明，Robo4 受体的激活会干扰多种通透性因子（包括 TNF-α、白细胞介素和凝血酶）的下游信号级联。我们克隆了 Slit2 的活性片段 Slit2N，它似乎与 Slit2 具有相同的功效，并且比天然蛋白更容易生产。 Navigen 已证明 Slit2N 可有效降低盲肠结扎和穿刺引起的败血症动物模型的死亡率。由于与蛋白质治疗相关的挑战，李博士试图鉴定一种可以以类似于 Slit2N 的方式影响 Robo4 通路的小分子。 Li 博士和合作者确定 Robo4 激活的关键下游步骤是抑制小 GTP 酶、ADP 核糖基化因子 6 (ARF6)。 Li博士及其同事进一步确定，可以使用小分子抑制剂NAV838通过抑制其ARF-GEF、细胞粘连蛋白2/ARNO来阻断ARF6。李博士的实验室与 Navigen 合作表明，通过阻断 ARF-GEF 或通过 Slit2N 抑制激活 Robo4 来抑制 ARF6，会产生类似的表型：抑制 VEGF 诱导的内皮细胞迁移。 Navigen 正在根据该申请寻求资金，以确认 Slit2N 在治疗脓毒症中的功效，并确定 NAV838 作为小分子是否可能是比 Slit2N 更可行的治疗脓毒症的方法。 Navigen 预计将这种优质化合物推进 IND 阶段，以最终实现商业化。拟议的研究旨在实现 3 个目标：1）开发由假单胞菌肺炎（PAP）引起的脓毒症动物模型，其中抗生素治疗剂量和时间滴定以实现约 50% 的 7 天死亡率，2）测试疗效并确定在 CLP 和 PAP 模型中 Slit2N 联合抗生素治疗的最有效剂量（目标 1 中建立的 PAP），3) 确定 NAV838 联合抗生素是否比联合抗生素具有更好的疗效Slit2N 加抗生素通过在 CLP 和 PAP 动物模型中进行测试。公共卫生相关性：脓毒症是一种临床综合征，由宿主和传染原之间复杂的相互作用引起，其特征是多种炎症途径的系统激活，包括细胞因子网络和凝血。与严重脓毒症相关的死亡率在 30% 至 50% 之间，脓毒症是手术患者和创伤受害者发病和死亡的主要原因。目前，尚无治疗脓毒症的有效疗法。