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- Title
Treatment of AG129 mice with antisense morpholino oligomers increases survival time following challenge with dengue 2 virus.
- Authors
David A. Stein; Claire Y.-H. Huang; Shawn Silengo; Adams Amantana; Stacy Crumley; Robert E. Blouch; Patrick L. Iversen; Richard M. Kinney; Stein, David A; Huang, Claire Y-H; Silengo, Shawn; Amantana, Adams; Crumley, Stacy; Blouch, Robert E; Iversen, Patrick L; Kinney, Richard M
- Abstract
<bold>Objectives: </bold>To determine the antiviral activity of phosphorodiamidate morpholino oligomers (PMO) and peptide-conjugated PMO (PPMO) in AG129 mice infected with dengue 2 virus (DENV-2).<bold>Methods: </bold>Antisense PMO and PPMO were designed against the 5' terminal region (5'SL) or the 3'-cyclization sequence region (3'CS) of DENV genomic RNA and administered to AG129 mice before and/or after infection with DENV-2. In addition, cell culture evaluations designed to determine optimum PPMO length, and pharmacokinetic and toxicity analysis of PPMO were also carried out.<bold>Results: </bold>Mock-treated AG129 mice lived for 9-17 days following intraperitoneal (ip) infection with 10(4)-10(6) pfu of DENV-2 (strain New Guinea C). Intraperitoneal administration of 5'SL or 3'CS PPMO before and after DENV infection produced an increase in the average survival time of up to 8 days. Animals receiving only post-infection PPMO treatment did not benefit significantly. Cell culture studies showed that PPMO of 22-24 bases long produced substantially higher DENV titre reductions than did PPMO that were either shorter or longer. Pharmacokinetic and toxicology analysis with non-infected animals showed that nine consecutive once-daily ip treatments of 10 mg/kg PPMO resulted in high concentrations of PPMO in the liver and caused little impact on overall health.<bold>Conclusions: </bold>The data indicate that PPMO had considerable antiviral efficacy against DENV-2 in the AG129 mouse model and that PPMO treatment early in the course of an infection was critical to extending the survival times of DENV-2-infected mice in the AG129 model system.
- Subjects
GEL permeation chromatography; CHROMATOGRAPHIC analysis; SEPHAROSE; RODENTS
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2008, Vol 62, Issue 3, p555
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkn221