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.
Dengue virus (DENV) infection is recognized as one of the most important mosquito-borne human infections in the 21th century. According to WHO, approximately 50 million people are actually infected each year with DENV with over 500,000 requiring hospitalization. Additionally, WHO reports that mortality rates among those affected by DENV are 2.5%. Once considered predominantly a tropical illness, the disease has spread into more temperate areas, and its incidence has increased 30-fold in the last 50 years.
