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

PPMO 拉沙病毒感染和疾病抑制剂在豚鼠模型中的评价

基本信息

批准号：
10402267
负责人：
Hong M Moulton
金额：
$ 7.43万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-07 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402267
关键词：
Address Africa Animal Model Animals Antisense Oligonucleotides Antiviral Agents Antiviral Therapy Appearance Arenavirus Behavior Biological Assay Biological Products Biological Warfare Body Temperature Body Weight Case Fatality Rates Category A pathogen Cavia Cell Culture Techniques Cells Cessation of life Clinical Clinical Trials Complementary RNA Conserved Sequence Contracts Country Data Development Disease Disease Outbreaks Dose Duchenne muscular dystrophy Evaluation Exhibits FDA approved Genetic Diseases Genomics Geography Goals Growth Guanosine Human In Vitro Incidence Infection Laboratories Lassa Fever Lassa virus Life Cycle Stages Measurement Medical Monitor Morbidity - disease rate National Institute of Allergy and Infectious Disease Nucleic Acids Outcome Patients Peptides Permeability Persons Plaque Assay Production Public Health RNA Sequences RNA Viruses Reagent Research Ribavirin Risk Single-Stranded DNA Standardization Temperature Testing Therapeutic Therapeutic Agents Tissues Toxic effect Vaccines Viral Viral Genome Viral Hemorrhagic Fevers Viral Pathogenesis Viral Proteins Virus Virus Diseases Virus Replication Weight analog anti-viral efficacy antiviral drug development base clinical development clinical efficacy design efficacy testing genomic RNA guinea pig model human disease in vivo in vivo Model inhibitor mortality multidisciplinary nucleic acid analog phosphorodiamidate morpholino oligomer prevent survivorship viral RNA

项目摘要

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.

一种PPMO抑制剂对拉沙病毒感染和疾病的豚鼠模型评价