The Ferret as a model for evaluation of antiviral efficacy against Venezuelan equine encephalitis virus

Project Summary Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne, New World Alphavirus that has caused several major epizootic and epidemic disease outbreaks in humans and equines in Latin America. In addition to natural mosquito-borne infection, the potential biothreat inherent in the ability to disseminate these viruses via the respiratory route has driven the development of antiviral drugs for this route of exposure. We propose to assess the pathogenesis of the ferret model of intranasal administration of VEEV INH in the ferret; VEEV INH is the proposed human reference challenge strain for vaccine and therapeutic development in animal models. We will assess the model’s potential for preclinical testing of antivirals using our lead antiviral, BDGR-354. We have extensively tested BDGR-354 in the mouse, which provided 100% protection by oral administration of BDGR354, prophylactically and therapeutically; and oral is the route proposed herein for administration of BDGR-354. Under the Animal Rule Regulatory pathway our PreIND submission for BDGR354, we must propose two animal models to demonstrate efficacy. Other small animal models of VEEV include hamsters and cotton rats, however, these models do not sufficiently recapitulate disease. An additional model is nonhuman primate (NHP), however, given the expense and scarcity of NHP, a ferret model for the neurotropic alphaviruses will be of great benefit to the antiviral community. Given that the ferret model is accepted by the FDA for safety and efficacy testing of influenza virus vaccines and therapeutics, we expect that that FDA will be supportive of this animal model. Hence, we propose to evaluate the virology and pathogenesis of the ferret model for VEEV-INH (aim 1), and we propose to use this model to evaluate the toxicity, prophylactic and therapeutic efficacy of BDGR-354 (aim 2). The proposed studies of intranasal infection of VEEV in ferret will provide new insights into the spatial and temporal dynamics of virus and pathogenesis. We hope the studies proposed with BDGR-354 in VEEV-ferret will provide a novel approach for preclinical studies in support of PreIND submissions for small molecules for the neurotrophic alphaviruses. Regardless of our success with BDGR-354, the studies will inform approaches in the development of novel therapeutic strategies in the ferret for the prevention or treatment of neurotropic alphavirus pathology.