Slit2N for the Treatment of Viral Hemorrhagic Fever

Slit2N 用于治疗病毒性出血热

• 批准号: 8535980
• 负责人: ALAN L MUELLER
• 金额: $ 81万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-14 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535980
• 关键词: Affect; Agonist; Animals; Antiviral Agents; Area; Avian Influenza; Blood Vessels; Cathepsin G; Cessation of life; Cleaved cell; Clinical Paths; Culicidae; Dengue; Dengue Hemorrhagic Fever; Dengue Shock Syndrome; Dengue Virus; Disease; Dose; Drosophila sli protein; Drug Kinetics; Ebola virus; Edema; Endothelium; Extravasation; Fever; Frankfurt-Marburg Syndrome Virus; Future; Hospitalization; Human; Immune system; In Vitro; Incidence; Infection; Injury; Interferon-alpha; Intramuscular; Lassa fever virus; Lead; Ligands; Methods; Mus; Neutrophil Activation; Organ failure; Outcome; Patients; Permeability; Play; Production; Proteins; Pulmonary Edema; Reporting; Role; Route; Safety; Schedule; Serine Protease; Shock; Staging; Testing; Time; Universities; Utah; Viral; Viral Hemorrhagic Fevers; Virus Diseases; Work; cadherin 5; cell bank; cytokine; hemorrhagic fever virus; in vivo; interest; large scale production; meetings; mortality; neutrophil; pancreatic elastase II; pre-clinical; prevent; receptor; research study; safety study; stable cell line; subcutaneous

DESCRIPTION (provided by applicant): Viral hemorrhagic fever (VHF) activates the innate immune system triggering an exuberant release of cytokines and other permeability factors that destabilize the endothelial barrier. The loss of vascular integrity results in non-cardiogenic edema, shock, multi-organ failure and death. The relationship between VHF- induced endothelial breakdown and mortality has been studied in multiple forms of hemorrhagic fever and it has been well established in dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) which are characterized by fever and vascular leakage resulting in non-cardiogenic pulmonary edema followed in severe cases by shock and death1. Navigen's scientific co-founder, Dr. Dean Li, identified an endothelial specific receptor, Robo4, that is expressed in mature vessels and is upregulated following endothelial injury from cytokine storm. Activation of Robo4's ligand, Slit protein, reduces agonist-induced vascular leak in vitro and in vivo by preventing the internalization of VE-cadherin2. Navigen believes that Slit2N may have broad-spectrum efficacy in the treatment of many VHFs as there is evidence that cytokine storm and resulting VE-cadherin internalization plays a role in the vascular leak associated with several hemorrhagic fever viruses in addition to DENV including Hanta, Ebola, and Marburg3, 4. Slit2N has been shown to prevent mortality from vascular leak in a number of other conditions associated with massive cytokine storm, including avian influenza and sepsis5. Identification of the most efficacious dose and dose schedule for Slit2N in treating DHF/DSS could lead to the first approved therapy to treat DHF/DSS and would set the stage for expanding testing to other forms of VHF In this project, we will complete the initial work necessary to initiate GMP production of Slit2N and complete initial PK studies to determine whether subcutaneous or intramuscular dosing of Slit2N can be an efficacious delivery method. We will also initiate preliminary safety studies and will identify the most efficacious dose of Slit2N in treating DHF/DSS in AG219 mice. These animals are interferon-alpha/beta and -gamma receptor deficient and the vascular leak in DHF/DSS is similar to the course of disease in humans. We will also test Slit2N in conjunction with the most promising available anti-viral in an effort to determine whether, as we hypothesize, Slit2N in combination with an anti-viral will result in better outcomes than with either therapy alone. With this information, we would then expect to meet with the FDA in a pre-IND meeting to discuss the final preclinical requirements and future clinical path.

描述(申请人提供)：病毒出血热(VHF)激活先天免疫系统，引发细胞因子和其他渗透因子的大量释放，破坏内皮屏障的稳定。血管完整性的丧失会导致非心源性水肿、休克、多器官衰竭和死亡。在多种形式的出血热中，已经研究了VHF引起的内皮破坏与死亡率的关系，并在登革出血热(DHF)和登革休克综合征(DSS)中得到了很好的证实，这两种疾病的特征是发热和血管渗漏导致非心源性肺水肿，严重者继之以休克和死亡1。Navigen的科学联合创始人Dean Li博士发现了一种内皮特异性受体Robo4，该受体在成熟的血管中表达，并在细胞因子风暴导致的内皮损伤后上调。激活Robo4的S配体，Sit蛋白，通过阻止VE-钙粘蛋白2的内化，在体外和体内减少激动剂诱导的血管泄漏。Navigen认为，Slit2N可能在治疗许多VHFs方面具有广泛的疗效，因为有证据表明，细胞因子风暴和由此产生的VE-钙粘素内化在除DENV之外的几种出血热病毒相关的血管泄漏中发挥作用，包括汉塔、埃博拉和Marburg3，4。Slit2N已被证明可以在许多其他与大规模细胞因子风暴相关的情况下防止血管泄漏死亡，包括禽流感和败血症5。确定Slit2N治疗DHF/DSS的最有效剂量和剂量时间表可能导致第一个被批准的治疗DHF/DSS的方法，并将为将测试扩展到其他形式的VHF奠定基础。在本项目中，我们将完成启动Slit2N的GMP生产所需的初步工作，并完成初步的PK研究，以确定Slit2N皮下或肌肉内剂量是否可以是一种有效的给药方法。我们还将启动初步的安全性研究，并确定Slit2N治疗AG219小鼠DHF/DSS的最有效剂量。这些动物缺乏干扰素-α/β和-伽马受体，DHF/DSS的血管泄漏与人类的病程相似。我们还将联合测试Slit2N和最有希望的现有抗病毒药物，以努力确定是否如我们假设的那样，Slit2N联合抗病毒药物将产生比单独使用任何一种疗法更好的结果。有了这些信息，我们预计将在IND前会议上与FDA会面，讨论最终的临床前要求和未来的临床路径。