Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs (original) (raw)
- Letter
- Published: 24 July 2005
- Jennifer A Lockridge1 na1,
- Lucinda Shaw1,
- Karin Blanchard1,
- Kristi Jensen1,
- Wendy Breen1,
- Kimberly Hartsough1,
- Lynn Machemer1,
- Susan Radka1,
- Vasant Jadhav1,
- Narendra Vaish1,
- Shawn Zinnen1,
- Chandra Vargeese1,
- Keith Bowman1,
- Chris S Shaffer1,
- Lloyd B Jeffs2,
- Adam Judge2,
- Ian MacLachlan2 &
- …
- Barry Polisky1
Nature Biotechnology volume 23, pages 1002–1007 (2005)Cite this article
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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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- David V Morrissey and Jennifer A Lockridge: These authors contributed equally to this work.
Authors and Affiliations
- 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 - Protiva Biotherapeutics, Inc., 100-3480 Gilmore Way, Burnaby, V5G 4Y1, British Columbia, USA
Lloyd B Jeffs, Adam Judge & Ian MacLachlan
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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
- Received: 28 March 2005
- Accepted: 17 June 2005
- Published: 24 July 2005
- Issue Date: 01 August 2005
- DOI: https://doi.org/10.1038/nbt1122