title: Minimal-length Synthetic shRNAs Formulated with Lipid Nanoparticles are Potent Inhibitors of Hepatitis C Virus IRES-linked Gene Expression in Mice.
abstract: We previously identified short synthetic shRNAs (sshRNAs) that target a conserved hepatitis C virus (HCV) sequence within the internal ribosome entry site (IRES) of HCV and potently inhibit HCV IRES-linked gene expression. To assess in vivo liver delivery and activity, the HCV-directed sshRNA SG220 was formulated into lipid nanoparticles (LNP) and injected i.v. into mice whose livers supported stable HCV IRES-luciferase expression from a liver-specific promoter. After a single injection, RNase protection assays for the sshRNA and (3)H labeling of a lipid component of the nanoparticles showed efficient liver uptake of both components and long-lasting survival of a significant fraction of the sshRNA in the liver. In vivo imaging showed a dose-dependent inhibition of luciferase expression (>90% 1 day after injection of 2.5 mg/kg sshRNA) with t1/2 for recovery of about 3 weeks. These results demonstrate the ability of moderate levels of i.v.-injected, LNP-formulated sshRNAs to be taken up by liver hepatocytes at a level sufficient to substantially suppress gene expression. Suppression is rapid and durable, suggesting that sshRNAs may have promise as therapeutic agents for liver indications.Molecular Therapy-Nucleic Acids (2013) 2, e123; doi:10.1038/mtna.2013.50; published online 17 September 2013.
authors.affiliation: SomaGenics, Inc., 2161 Delaware Ave., Santa Cruz, California, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Dallas
authors.forename: Heini
authors.initials: H
authors.lastname: Ilves
authors.forename: Joshua
authors.initials: J
authors.lastname: Shorenstein
authors.forename: Adam
authors.initials: A
authors.lastname: Judge
authors.forename: Ryan
authors.initials: R
authors.lastname: Spitler
authors.forename: Christopher
authors.initials: C
authors.lastname: Contag
authors.forename: Suet Ping
authors.initials: SP
authors.lastname: Wong
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harbottle
authors.forename: Ian
authors.initials: I
authors.lastname: Maclachlan
authors.forename: Brian H
authors.initials: BH
authors.lastname: Johnston
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