Treatment of HCV Infection by Targeting MicroRNA
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- 2 May 2013
- journal article
- research article
- Published by Massachusetts Medical Society in New England Journal of Medicine
- Vol. 368 (18), 1685-1694
- https://doi.org/10.1056/nejmoa1209026
Abstract
The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid–modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function. In this phase 2a study at seven international sites, we evaluated the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization. Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the miravirsen groups, the mean maximum reduction in HCV RNA level (log10 IU per milliliter) from baseline was 1.2 (P=0.01) for patients receiving 3 mg per kilogram, 2.9 (P=0.003) for those receiving 5 mg per kilogram, and 3.0 (P=0.002) for those receiving 7 mg per kilogram, as compared with a reduction of 0.4 in the placebo group. During 14 weeks of follow-up after treatment, HCV RNA was not detected in one patient in the 5-mg group and in four patients in the 7-mg group. We observed no dose-limiting adverse events and no escape mutations in the miR-122 binding sites of the HCV genome. The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance. (Funded by Santaris Pharma; ClinicalTrials.gov number, NCT01200420.)Keywords
This publication has 29 references indexed in Scilit:
- Association Between Sustained Virological Response and All-Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic FibrosisJama-Journal Of The American Medical Association, 2012
- Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1The New England Journal of Medicine, 2012
- Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus InfectionThe New England Journal of Medicine, 2011
- Boceprevir for Untreated Chronic HCV Genotype 1 InfectionThe New England Journal of Medicine, 2011
- Outcome of sustained virological responders with histologically advanced chronic hepatitis CHepatology, 2010
- Liver Transplantation in the United States, 1999-2008American Journal of Transplantation, 2010
- microRNA-122 stimulates translation of hepatitis C virus RNAThe EMBO Journal, 2008
- Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNAScience, 2005
- The functions of animal microRNAsNature, 2004
- MicroRNAs: Genomics, Biogenesis, Mechanism, and FunctionCell, 2004