In vivo screening of modified siRNAs for non-specific antiviral effect in a small fish model: number and localization in the strands are important

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  • Brian Dall Schyth, Department of Poultry, Fish and Fur Animals, National Veterinary Institute, Technical University of Denmark, Danmark
  • Jesper Bertram Bramsen
  • Malgorzata Maria Pakula
  • ,
  • Sekar Larashati, Department of Poultry, Fish and Fur Animals, National Veterinary Institute, Technical University of Denmark, Danmark
  • Jørgen Kjems
  • Jesper Wengel, Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, Danmark
  • Niels Lorenzen, Department of Poultry, Fish and Fur Animals, National Veterinary Institute, Technical University of Denmark, Danmark
Small interfering RNAs (siRNAs) are promising new active compounds in gene medicine but the induction of non-specific immune responses following their delivery continues to be a serious problem. With the purpose of avoiding such effects chemically modified siRNAs are tested in screening assay but often only examining the expression of specific immunologically relevant genes in selected cell populations typically blood cells from treated animals or humans. Assays using a relevant physiological state in biological models as read-out are not common. Here we use a fish model where the innate antiviral effect of siRNAs is functionally monitored as reduced mortality in challenge studies involving an interferon sensitive virus. Modifications with locked nucleic acid (LNA), altritol nucleic acid (ANA) and hexitol nucleic acid (HNA) reduced the antiviral protection in this model indicative of altered immunogenicity. For LNA modified siRNAs, the number and localization of modifications in the single strands was found to be important and a correlation between antiviral protection and the thermal stability of siRNAs was found. The previously published sisiRNA will in some sequences, but not all, increase the antiviral effect of siRNAs. The applied fish model represents a potent tool for conducting fast but statistically and scientifically relevant evaluations of chemically optimized siRNAs with respect to non-specific antiviral effects in vivo.
OriginalsprogEngelsk
TidsskriftNucleic Acids Research
Vol/bind40
Nummer10
Sider (fra-til)4653-4665
Antal sider12
ISSN0305-1048
DOI
StatusUdgivet - jul. 2012

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