Nature Biotechnology
23, 1002 - 1007 (2005)
Published online: 24 July 2005; | doi:10.1038/nbt1122
Potent and persistent in vivo anti-HBV activity of chemically modified siRNAsDavid V Morrissey1, 3, Jennifer A Lockridge1, 3, 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 Polisky11
Sirna Therapeutics, Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA. 2
Protiva Biotherapeutics, Inc., 100-3480 Gilmore Way, Burnaby, British Columbia V5G 4Y1, USA. 3
These authors contributed equally to this work.
Correspondence should be addressed to David V Morrissey morrisseyd@sirna.com 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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