Animal Model Core

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ABSTRACT Assessing and optimizing the treatment efficacy of novel leads against SARS CoV-2, other coronaviruses and additional RNA viruses of pandemic concern in animal models is crucial for advancing compounds to the preclinical stage of development. Currently, there is a paucity of reproducible disease models with reliable metrics to assess lead compounds and even fewer facilities and personnel with the expertise to perform these essential studies. To meet this critical challenge, the MAVDA Animal Model Core will provide validated and reproducible pulmonary infection models in rodents under biosafety level 3 (BSL-3) containment for SARS CoV- 2 and other coronaviruses including MERS. These pulmonary infection models utilize transgenic mice expressing hACE2 (K18-hACE2) or hDPP4 (K18-hDPP4) and Outbred Golden Syrian Hamsters that display a range of disease pathology observed clinically with these Coronaviruses. Other rodent models will be made available to assess leads against other clinically important Toga- and Flavi- RNA viruses. The Aims of the core are to: 1) provide small animal pulmonary infection models for SARS CoV-2, other Coronaviruses (SARS CoV and MERS), clinically relevant disease models for other RNA viruses of pandemic concern, and to rapidly evaluate lead compounds, and 2) advance leads to the pre-clinical stage of development by performing pharmacodynamic response and dose optimization studies in the described animal infection models. The Animal Model Core under the direction of Dr. David Perlin is highly experienced and previously served as a multi-institutional regional animal core providing BSL-3 animal models for the Region II Regional Center of Excellent (RCE; Northeast Biodefense Center) for 10 years (2003-2013) and one of the NIH Center of Excellence for Translational Research (CETRs) for the past 8 years (2013 to present). The Animal Core operates at a very high capacity, having logged more than 3.0 million animal days of BSL-3 high threat bacterial and viral pathogens since 2003. An experienced and dedicated high containment animal model team can perform small animal pulmonary infection models with multiple routes of treatment (oral, subcutaneous, intramuscular) and markers for disease (morbidity/mortality, microbial burden, histopathology, etc.) Output measures include daily weight loss, nasal wash, lung and other vital organ viral burdens (TCID50; qPCR, PFU), and histopathological analysis at key sites of infection. The management staff of the Animal Model Core works closely with both the project leadership and other Core Directors (e.g., Pharmacology and Virology) to ensure all novel leads are rapidly vetted through the development pipeline. This close and constant line of communication permits the necessary adjustments in study design and execution and has resulted in the advancement of 7 promising leads in the RU- CDI CETR projects from 2013 to 2021. The Animal Model Core possesses cutting edge instrumentation in the high containment lab for analysis of infections and therapeutic responses. All services can be performed under high-level biocontainment with regulatory approval.