title: Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs.
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.
authors.affiliation: Sirna Therapeutics, Inc., 2950 Wilderness Place, Boulder, Colorado 80301, USA. morrisseyd@sirna.com
authors.forename: David V
authors.initials: DV
authors.lastname: Morrissey
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lockridge
authors.forename: Lucinda
authors.initials: L
authors.lastname: Shaw
authors.forename: Karin
authors.initials: K
authors.lastname: Blanchard
authors.forename: Kristi
authors.initials: K
authors.lastname: Jensen
authors.forename: Wendy
authors.initials: W
authors.lastname: Breen
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hartsough
authors.forename: Lynn
authors.initials: L
authors.lastname: Machemer
authors.forename: Susan
authors.initials: S
authors.lastname: Radka
authors.forename: Vasant
authors.initials: V
authors.lastname: Jadhav
authors.forename: Narendra
authors.initials: N
authors.lastname: Vaish
authors.forename: Shawn
authors.initials: S
authors.lastname: Zinnen
authors.forename: Chandra
authors.initials: C
authors.lastname: Vargeese
authors.forename: Keith
authors.initials: K
authors.lastname: Bowman
authors.forename: Chris S
authors.initials: CS
authors.lastname: Shaffer
authors.forename: Lloyd B
authors.initials: LB
authors.lastname: Jeffs
authors.forename: Adam
authors.initials: A
authors.lastname: Judge
authors.forename: Ian
authors.initials: I
authors.lastname: MacLachlan
authors.forename: Barry
authors.initials: B
authors.lastname: Polisky
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D018390:Gene Targeting / Q000379:methods; D015316:Genetic Therapy / Q000379:methods; D006509:Hepatitis B / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D020099:Coated Materials, Biocompatible; D008081:Liposomes; D034741:RNA, Small Interfering