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Gastroenterology. 2014 Jan;146(1):63-6.e5. doi: 10.1053/j.gastro.2013.09.049. Epub 2013 Sep 27.

Formulated minimal-length synthetic small hairpin RNAs are potent inhibitors of hepatitis C virus in mice with humanized livers.

Author information

1
Hoffmann-La Roche, Nutley, New Jersey.
2
SomaGenics, Inc, Santa Cruz, California.
3
Tekmira Pharmaceuticals, Burnaby, British Columbia, Canada.
4
SomaGenics, Inc, Santa Cruz, California. Electronic address: bjohnston@somagenics.com.

Abstract

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.

KEYWORDS:

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

PMID:
24076507
PMCID:
PMC3896324
DOI:
10.1053/j.gastro.2013.09.049
[Indexed for MEDLINE]
Free PMC Article
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