Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs |
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Authors: | Morrissey David V Lockridge Jennifer A Shaw Lucinda Blanchard Karin Jensen Kristi Breen Wendy Hartsough Kimberly Machemer Lynn Radka Susan Jadhav Vasant Vaish Narendra Zinnen Shawn Vargeese Chandra Bowman Keith Shaffer Chris S Jeffs Lloyd B Judge Adam MacLachlan Ian Polisky Barry |
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Institution: | Sirna Therapeutics, Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA. morrisseyd@sirna.com |
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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 log(10). 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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