Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection.
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.
Lanford
Robert E
RE
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
ES
Petri
Andreas
A
Persson
Robert
R
Lindow
Morten
M
Munk
Martin E
ME
Kauppinen
Sakari
S
Ørum
Henrik
H
D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D054357:Chemokine CXCL10 / Q000097:blood; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D007372:Interferons / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000821:virology; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides; D002679:Pan troglodytes; D054735:Phosphorothioate Oligonucleotides / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy
D000998:Antiviral Agents; D054357:Chemokine CXCL10; D035683:MicroRNAs; D009841:Oligonucleotides; D054735:Phosphorothioate Oligonucleotides; D012333:RNA, Messenger; D012367:RNA, Viral; D007372:Interferons; D002784:Cholesterol; C581159:miravirsen