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PMID: 19965718 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection.

Science (New York, N.Y.) ·Vol. 327 ·No. 5962 ·2010-01-08 ·Pages 198-201

Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, Kauppinen S, Ørum H

Abstract

The liver-expressed microRNA-122 (miR-122) is essential for hepatitis C virus (HCV) RNA accumulation in cultured liver cells, but its potential as a target for antiviral intervention has not been assessed. We found that treatment of chronically infected chimpanzees with a locked nucleic acid (LNA)-modified oligonucleotide (SPC3649) complementary to miR-122 leads to long-lasting suppression of HCV viremia, with no evidence of viral resistance or side effects in the treated animals. Furthermore, transcriptome and histological analyses of liver biopsies demonstrated derepression of target mRNAs with miR-122 seed sites, down-regulation of interferon-regulated genes, and improvement of HCV-induced liver pathology. The prolonged virological response to SPC3649 treatment without HCV rebound holds promise of a new antiviral therapy with a high barrier to resistance.

MeSH Terms
Animals Antiviral Agents/adverse effects,blood,therapeutic use Chemokine CXCL10/blood Cholesterol/blood Disease Models, Animal Drug Evaluation, Preclinical Drug Resistance, Viral Female Gene Expression Profiling Gene Expression Regulation Hepacivirus/drug effects,genetics,isolation & purification,physiology Hepatitis C, Chronic/drug therapy,genetics,virology Interferons/metabolism Liver/metabolism,virology Male MicroRNAs/antagonists & inhibitors,genetics,metabolism Oligonucleotides Pan troglodytes Phosphorothioate Oligonucleotides/adverse effects,blood,therapeutic use RNA, Messenger/genetics,metabolism RNA, Viral/metabolism Viral Load Viremia/drug therapy
Chemicals
Antiviral Agents Chemokine CXCL10 MicroRNAs Oligonucleotides Phosphorothioate Oligonucleotides RNA, Messenger RNA, Viral Interferons Cholesterol miravirsen
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Lanford Robert E
Department of Virology and Immunology and Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA.
Hildebrandt-Eriksen Elisabeth S
Petri Andreas
Persson Robert
Lindow Morten
Munk Martin E
Kauppinen Sakari
Ørum Henrik
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1178178
Published
2010-01-08
Epub
2009-00-03
Pages
198-201
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3436126
Subset
IM
Grants
NCRR NIH HHS · P51 RR13986 · United States
NCRR NIH HHS · C06 RR012087 · United States
NCRR NIH HHS · P51 RR013986 · United States
NCRR NIH HHS · C06 RR012087-01 · United States
NCRR NIH HHS · C06 RR 12087 · United States
Databases
GEO
GSE18919
Corrections
CommentIn
PMID: 20373371
External Links
PubMed source DOI: 10.1126/science.1178178 PMC Full Text View journal details
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