Miravirsen dosing in chronic hepatitis C patients results in decreased microRNA-122 levels without affecting other microRNAs in plasma.
BACKGROUND
MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus replication. Administration of miravirsen, an anti-miR-122 oligonucleotide, resulted in a dose dependent and prolonged decrease in HCV RNA levels in chronic hepatitis C patients.


OBJECTIVE
To assess the plasma level of various miRNAs in patients dosed with miravirsen.


METHODS
We included 16 of 36 chronic hepatitis C patients who received five injections of either 3 mg/kg (n = 4), 5 mg/kg (n = 4), 7 mg/kg (n = 4) miravirsen or placebo (n = 4) over a 4-week period in a double-blind, randomised phase 2a study. Plasma levels of 179 miRNAs were determined by qPCR and compared between patients dosed with miravirsen or placebo.


RESULTS
Median plasma miR-122 level at baseline in patients receiving miravirsen was 3.9 × 10(3) compared to 1.3 × 10(4) copies/4 μL in placebo-dosed patients (P = 0.68). At week 1, 4, 6 and 10/12, patients dosed with miravirsen had respectively a median 72-fold, 174-fold, 1109-fold and 552-fold lower expression of miR-122 than at baseline (P = 0.001, as compared to patients receiving placebo). At week 4 of dosing, miRNA-profiling demonstrated a significant lower expression of miR-210 and miR-532-5p compared to baseline (3.0 and 4.7-fold lower respectively). However, subsequent longitudinal analysis showed no significant differences in miR-210 and miR-532-5p plasma levels throughout the study period.


CONCLUSIONS
We demonstrated a substantial and prolonged decrease in plasma miR-122 levels in patients dosed with miravirsen. Plasma levels of other miRNAs were not significantly affected by antagonising miR-122.
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.|Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
M H
MH
van der Ree
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
A J
AJ
van der Meer
Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
A C
AC
van Nuenen
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
J
J
de Bruijne
Santaris Pharma A/S, Hørsholm, Denmark.
S
S
Ottosen
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.|Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada.
H L
HL
Janssen
Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
N A
NA
Kootstra
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.|Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
H W
HW
Reesink
D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D008875:Middle Aged; D009841:Oligonucleotides / Q000494:pharmacology* / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction
C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; C581159:miravirsen