Slit2N for the Treatment of Viral Hemorrhagic Fever

描述（由申请方提供）：病毒性出血热（VHF）激活先天免疫系统，引发细胞因子和其他渗透性因子的大量释放，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、多器官衰竭和死亡。已在多种形式的出血热中研究了VHF诱导的内皮破裂与死亡率之间的关系，并已在登革出血热（DHF）和登革休克综合征（DSS）中得到充分确立，其特征为发热和血管渗漏，导致非心源性肺水肿，严重病例随后发生休克和死亡1。Navigen的科学联合创始人Dean Li博士确定了一种内皮特异性受体Robo 4，该受体在成熟血管中表达，并在细胞因子风暴导致内皮损伤后上调。Robo 4的配体Slit蛋白的激活通过阻止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渗漏。Navigen认为，Slit 2N可能在治疗许多VHF方面具有广谱疗效，因为有证据表明，细胞因子风暴和导致的VE-钙粘蛋白内化在与除DENV外的几种出血热病毒（包括汉坦病毒、埃博拉病毒和马尔堡病毒）相关的血管渗漏中发挥作用3，4。Slit 2N已被证明可以预防与大量细胞因子风暴相关的许多其他疾病（包括禽流感和败血症）中血管渗漏导致的死亡。确定Slit 2N治疗DHF/DSS的最有效剂量和剂量方案可能导致治疗DHF/DSS的第一个批准的疗法，并为将测试扩展到其他形式的VHF奠定基础。我们将完成启动Slit 2N GMP生产所需的初步工作，并完成初步PK研究，以确定皮下或肌内给药Slit 2N是否有效。交付方式我们还将启动初步安全性研究，并将确定Slit 2N治疗AG 219小鼠DHF/DSS的最有效剂量。这些动物是干扰素-α/β和-γ受体缺陷的，DHF/DSS中的血管渗漏与人类的疾病过程相似。我们还将测试Slit 2N与最有希望的抗病毒药物联合使用，以确定是否如我们假设的那样，Slit 2N与抗病毒药物联合使用将比单独使用任何一种治疗产生更好的结果。有了这些信息，我们将在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。

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.