Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs (original) (raw)

Nature Biotechnology volume 23, pages 1002–1007 (2005)Cite this article

Abstract

The efficacy of lipid-encapsulated, chemically modified short interfering RNA (siRNA) targeted to hepatitis B virus (HBV) was examined in an in vivo mouse model of HBV replication. Stabilized siRNA targeted to the HBV RNA was incorporated into a specialized liposome to form a stable nucleic-acid-lipid particle (SNALP) and administered by intravenous injection into mice carrying replicating HBV. The improved efficacy of siRNA-SNALP compared to unformulated siRNA correlates with a longer half-life in plasma and liver. Three daily intravenous injections of 3 mg/kg/day reduced serum HBV DNA >1.0 log10. The reduction in HBV DNA was specific, dose-dependent and lasted for up to 7 d after dosing. Furthermore, reductions were seen in serum HBV DNA for up to 6 weeks with weekly dosing. The advances demonstrated here, including persistence of in vivo activity, use of lower doses and reduced dosing frequency are important steps in making siRNA a clinically viable therapeutic approach.

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Acknowledgements

The authors would like to thank Roger Aitchison for statistical analysis, and Adrianna Wells for manuscript preparation.

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  1. David V Morrissey and Jennifer A Lockridge: These authors contributed equally to this work.

Authors and Affiliations

  1. Sirna Therapeutics, Inc., 2950 Wilderness Place, Boulder, 80301, Colorado, USA
    David V Morrissey, Jennifer A Lockridge, Lucinda Shaw, Karin Blanchard, Kristi Jensen, Wendy Breen, Kimberly Hartsough, Lynn Machemer, Susan Radka, Vasant Jadhav, Narendra Vaish, Shawn Zinnen, Chandra Vargeese, Keith Bowman, Chris S Shaffer & Barry Polisky
  2. Protiva Biotherapeutics, Inc., 100-3480 Gilmore Way, Burnaby, V5G 4Y1, British Columbia, USA
    Lloyd B Jeffs, Adam Judge & Ian MacLachlan

Authors

  1. David V Morrissey
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  2. Jennifer A Lockridge
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  3. Lucinda Shaw
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  4. Karin Blanchard
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  5. Kristi Jensen
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  6. Wendy Breen
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  7. Kimberly Hartsough
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  8. Lynn Machemer
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  9. Susan Radka
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  10. Vasant Jadhav
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  11. Narendra Vaish
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  12. Shawn Zinnen
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  13. Chandra Vargeese
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  14. Keith Bowman
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  15. Chris S Shaffer
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  16. Lloyd B Jeffs
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  17. Adam Judge
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  18. Ian MacLachlan
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  19. Barry Polisky
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Correspondence toDavid V Morrissey.

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Morrissey, D., Lockridge, J., Shaw, L. et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs.Nat Biotechnol 23, 1002–1007 (2005). https://doi.org/10.1038/nbt1122

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