Formulated minimal-length synthetic small hairpin RNAs are potent inhibitors of hepatitis C virus in mice with humanized livers.
Short synthetic hairpin RNAs (sshRNAs) (SG220 and SG273) that target the internal ribosome entry site of the hepatitis C virus (HCV) were formulated into lipid nanoparticles and administered intravenously to HCV-infected urokinase plasminogen activator-severe combined immunodeficient mice with livers repopulated with human hepatocytes (humanized livers). Weekly administration of 2.5 mg/kg of each sshRNA for 2 weeks resulted in a maximal mean reduction in viral load of 2.5 log10 from baseline. The viral load remained reduced by more than 90% at 14 days after the last dose was given. The sshRNAs were well tolerated and did not significantly increase liver enzyme levels. These findings indicate the in vivo efficacy of a synthetic RNA inhibitor against the HCV genome in reducing HCV infection.
Hoffmann-La Roche, Nutley, New Jersey.
Han
H
Ma
SomaGenics, Inc, Santa Cruz, California.
Anne
A
Dallas
SomaGenics, Inc, Santa Cruz, California.
Heini
H
Ilves
SomaGenics, Inc, Santa Cruz, California.
Joshua
J
Shorenstein
Tekmira Pharmaceuticals, Burnaby, British Columbia, Canada.
Ian
I
MacLachlan
Hoffmann-La Roche, Nutley, New Jersey.
Klaus
K
Klumpp
SomaGenics, Inc, Santa Cruz, California. Electronic address: bjohnston@somagenics.com.
Brian H
BH
Johnston
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002678:Chimera; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects*; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles; D034741:RNA, Small Interfering / Q000494:pharmacology*; D019562:Viral Load / Q000187:drug effects*
D000998:Antiviral Agents; D034741:RNA, Small Interfering; C586432:SG220 compound; C586433:SG273 compound
HCV; IRES; LNP; PBS; RNA Interference; RNA interference; RNAi; RPA; Short shRNA; hepatitis C virus; internal ribosome entry site; lipid nanoparticle; phosphate-buffered saline; ribonuclease protection assay; short synthetic hairpin RNA; siRNA; sshRNA; uPA-SCID; uPA-SCID Chimeric Mice; urokinase-type plasminogen activator-severe combined immunodeficiency