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Antiviral
Agents as Therapy for SARS Collaborating Institution: University of Texas Medical Branch at Galveston (UTMB), Galveston, TX
Principal Investigator: Chien-te “Kent” Tseng
Expected Product: Therapeutics for severe acute respiratory syndrome caused by coronavirus.
Description: Severe acute respiratory syndrome (SARS) is a highly contagious respiratory disease caused by a novel human coronavirus (CoV), designated SARS-CoV. Although there have been no new reported field cases since 2003, this virus continues to exist in the nature, posing a threat for its return. To date, effective therapeutic measures against SARS are not available, thus making the development of effective antiviral therapy and vaccines imperative. The main objective of this application is to establish effective antiviral therapy against future SARS outbreaks. Animal models are critical for preclinical evaluation of the safety, immunogenicity, and efficacy of candidate antiviral drugs and vaccines. To establish an economical animal model for SARS-CoV infection, we generated transgenic mouse lineages expressing human angiotensin converting enzyme 2 (hACE2), a functional receptor of SARS-CoV. Importantly, these hACE2 transgenic lineages were highly susceptible to SARS-CoV infection, showing consistent clinical manifestations and death, making them superior to existing models described for SARS (i.e., nonhuman primates, ferrets, hamsters, and mice). Among several transgenic lineages, the AC70 lineage is the best characterized with regard to the infectivity and tissue of SARS-CoV, clinical manifestations, histopathology, inflammatory responses, and mortality, in response to infection. To accomplish this objective, I propose in this application to evaluate the therapeutic efficacy of some antiviral agents, including interferons (i.e., IFN-? and IFN-?), ribavirin, and immune plasma, in this innovative and highly sensitive transgenic mouse model. These antiviral agents are selected, because they were used empirically in treating SARS patients, resulting in anecdotal benefits during the explosive outbreak in 2002-2003. Their anti-SARS efficacy alone or in combination will be carefully assessed in a highly randomized and controlled fashion in these transgenic mice, using clinical, virological, pathological, and inflammatory changes, along with the mortality as criteria. If applicable, I will extend this project to include new lead compounds, such as protease inhibitors, compounds that prevent viral entry, siRNA for SARS-CoV replication, and vaccines that warrant inclusion in this study. Four specific aims are proposed: Upon completion of proposed studies, with close and productive mentor-trainee interactions, I anticipate not only gaining extensive scientific knowledge and hands-on experience in antiviral testing, but also research results identifying effective anti-SARS therapies.
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