Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs
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, Lloyd B Jeffs, Adam Judge, Ian MacLachlan, Barry Polisky, 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, Lloyd B Jeffs, Adam Judge, Ian MacLachlan, Barry Polisky
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.
Source: PubMed