Miravirsen dosing in chronic hepatitis C patients results in decreased microRNA-122 levels without affecting other microRNAs in plasma

作者：van der Ree M H^*; van der Meer A J; van Nuenen A C; de Bruijne J; Ottosen S; Janssen H L; Kootstra N A; Reesink H W

来源：Alimentary Pharmacology and Therapeutics, 2016, 43(1): 102-113.

DOI：10.1111/apt.13432

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.
Aim
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 x 10(3) compared to 1.3 x 10(4) copies/4 mu L 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.

• 出版日期2016-1