Evaluation of a PPMO Inhibitor of Lassa Virus Infection and Disease in a Guinea Pig Model

Evaluation of a PPMO Inhibitor of Lassa Virus Infection and Disease in a Guinea Pig Model ABSTRACT: Lassa fever (LF) is caused by infection with Lassa virus (LASV), and is currently a major human disease problem in much of West Africa, causing thousands of deaths annually. Recent outbreaks of LF have been characterized by an increased number of cases and larger geographic footprint compared to previous outbreaks, and constitute a burgeoning public health crisis. In addition, the number of LF cases imported into non-endemic countries is growing, and there is also concern that LASV could be used as an agent of biological warfare. There is as yet no licensed vaccine or specific antiviral therapeutic to intervene against LASV-infections and treat patients with LF, and current treatment options have poor efficacy. There is therefore an immediate and critical medical need for new antiviral compounds to address LASV. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are a class of single-stranded-nucleic acid analogs that can enter cells readily and interfere with the production of viral proteins through steric blocking of complementary RNA. PPMO have shown considerable antiviral efficacy in vitro and in vivo against a number of RNA viruses, including several arenaviruses. We propose to synthesize two PPMO targeting highly conserved RNA sequences in the genomic termini of the LASV genome. Each PPMO will be tested in a non-cytotoxic dose-range for antiviral activity against several genetically- disparate strains of LASV. The PPMO exhibiting the highest antiviral efficacy in vitro will then be advanced to testing in a guinea pig model of LASV disease. Animal weight, temperature, appearance and behavior, along with mortality and viral titer in several tissues will be monitored. This study is designed to evaluate the ability of PPMO to reduce morbidity and mortality in a small-animal model of of severe LASV-disease. If successful, the project will produce an inhibitor that would be immediately useful as a research reagent against any strain of LASV and as a candidate for further development as a therapeutic agent against LASV infections in humans.