Slit2N for the Treatment of Viral Hemorrhagic Fever

Slit2N 用于治疗病毒性出血热

基本信息

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
项目类别：
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

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

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项目摘要

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（由申请人提供）：病毒出血热（VHF）激活先天免疫系统，触发细胞因子的旺盛释放和其他渗透性因子，从而破坏内皮屏障的稳定性。血管完整性的丧失导致非心源性水肿，休克，多器官故障和死亡。 VHF诱导的内皮崩溃与死亡率之间的关系已以多种形式的出血热进行了研究，并且在登革热出血热（DHF）（DHF）和登革热休克综合征（DSS）中已经建立了良好的建立，这些（DSS）的特征在于，这些特征是在严重的肺部严重造成严重的肺部和死亡中，其特征是发烧和血管渗漏。 Navigen的科学共同创始人Dean Li博士确定了一种内皮特异性受体Robo4，该受体在成熟的血管中表达，并在细胞因子风暴内内皮损伤后被上调。 Robo4配体的激活，狭缝蛋白，通过防止VE-Cadherin2的内在化来减少激动剂诱导的体外和体内血管泄漏。 Navigen认为SLIT2N在许多VHF的治疗中可能具有广泛的功效，因为有证据表明，细胞因子风暴和由此导致的VE-辅助蛋白内在化在血管泄漏中起作用与几种出血热病毒相关的血管泄漏起着作用，除了Hanta，Ebola和Marburg3，Marburg3，slit2n的其他频率与其他相关的情况相关联。细胞因子风暴，包括禽流感和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有效的交付方法。我们还将启动初步的安全研究，并将确定在AG219小鼠中治疗DHF/DSS时最有效的SLIT2N剂量。这些动物是干扰素 - α/β和-gamma受体缺陷，DHF/DSS中的血管泄漏与人类疾病的进程相似。我们还将与最有希望的抗病毒一起测试SLIT2N，以确定与单独使用任何一种疗法相比，与我们假设的SLIT2N与抗病毒的结合是否会导致更好的结局。借助此信息，我们希望在预定的会议上与FDA会面，以讨论最终的临床前要求和未来的临床路径。