The four serotypes of dengue virus (DENV) circulate in more than 100 countries, resulting in an estimated 90 million cases of disease. Among these persons with dengue disease are patients who develop acute capillary permeability resulting in internal fluid losses that if not corrected may lead to shock, hemorrhage, and death. The outcome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), is widely attributed to pathological pharmacologic mediators, as serious endothelial damage lasts for a matter of hours and is rapidly reversed. Early identification of individuals suffering from fluid loss should lead to appropriate fluid replacement that stabilizes the situation. Given the immense burden of symptomatic dengue in the world, it is not surprising that there are treatment failures?an estimated 20,000 persons die of dengue each year. Research in humans has revealed a pattern of angiogenic factors that accompany the shock syndrome. Among these are vascular endothelial growth factor (VEGF) and angiopoietin (Ang)- 1/Ang-2. A mouse model, developed in our laboratory, and widely used by others, recapitulates DHF/DSS, including capillary leakage leading to hemoconcentration, shock and death. As shown by our preliminary data, DENV-infected mice have elevated levels of VEGF and Ang-2, and treatment of mice with a small molecule drug that targets the VEGF pathway, which is involved in regulating endothelial cell stability and barrier function, protects mice from lethal DENV challenge. Based on these data, we hypothesize that targeting the VEGF and/or Ang-1/Ang-2 pathway will protect mice against DENV disease pathogenesis. To test this hypothesis, we propose the following Specific Aims: 1. To investigate whether inhibition of the VEGF pathway protects the host against DENV disease pathogenesis. 2. To investigate whether manipulation of the Ang-1/Ang-2 pathway protects the host against DENV disease pathogenesis.
Safe and effective therapeutics against DENV are urgently needed, as global endemic regions are expanding, there is broader circulation of different DENV serotypes/genotypes, and phase IIb and III clinical trial results of the most advanced DENV vaccine candidate have been disappointing. This proposal focuses on the development of host response-based drugs that will be effective against any DENV serotype/genotype and minimize selection of drug-resistant DENV. Completion of this project will allow us to develop inexpensive, small molecule drugs (some of which have already been tested in humans). Additionally, it will allow us to partner with companies and other academic/non-profit institutions for developing multi-specific biologics with greater specificity and longer half-life than small molecules. By understanding the role of angiogenesis factors in DENV pathogenesis, we may identify drugs that protect against DENV and other hemorrhagic fever viruses.
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