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

Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne New World Alphavirus that has caused several majorepizootic and epidemic disease outbreaks in humans and equines in Latin America. In addition to natural mosquito-borneinfection the potential biothreat inherent in the ability to disseminate these viruses via the respiratory route has driven thedevelopment of antiviral drugs for this route of exposure. We propose to assess the pathogenesis of the ferret model ofintranasal administration of VEEV INH in the ferret; VEEV INH is the proposed human reference challenge strain forvaccine and therapeutic development in animal models. We will assess the models potential for preclinical testing ofantivirals 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 hereinfor administration of BDGR-354. Under the Animal Rule Regulatory pathway our PreIND submission for BDGR354 wemust propose two animal models to demonstrate efficacy. Other small animal models of VEEV include hamsters and cottonrats 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 tothe antiviral community. Given that the ferret model is accepted by the FDA for safety and efficacy testing of influenzavirus vaccines and therapeutics we expect that that FDA will be supportive of this animal model. Hence we propose toevaluate the virology and pathogenesis of the ferret model for VEEV-INH (aim 1) and we propose to use this model toevaluate the toxicity prophylactic and therapeutic efficacy of BDGR-354 (aim 2). The proposed studies of intranasalinfection of VEEV in ferret will provide new insights into the spatial and temporal dynamics of virus and pathogenesis. Wehope the studies proposed with BDGR-354 in VEEV-ferret will provide a novel approach for preclinical studies in supportof PreIND submissions for small molecules for the neurotrophic alphaviruses. Regardless of our success with BDGR-354the studies will inform approaches in the development of novel therapeutic strategies in the ferret for the prevention ortreatment of neurotropic alphavirus pathology.