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Treatment of HCV infection by targeting microRNA.

Publication ,  Journal Article
Janssen, HLA; Reesink, HW; Lawitz, EJ; Zeuzem, S; Rodriguez-Torres, M; Patel, K; van der Meer, AJ; Patick, AK; Chen, A; Zhou, Y; Persson, R ...
Published in: N Engl J Med
May 2, 2013

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

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Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

May 2, 2013

Volume

368

Issue

18

Start / End Page

1685 / 1694

Location

United States

Related Subject Headings

  • RNA, Viral
  • Oligonucleotides
  • Mutation
  • Middle Aged
  • MicroRNAs
  • Male
  • Injections, Subcutaneous
  • Humans
  • Hepatitis C, Chronic
  • Hepacivirus
 

Citation

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Janssen, H. L. A., Reesink, H. W., Lawitz, E. J., Zeuzem, S., Rodriguez-Torres, M., Patel, K., … Hodges, M. R. (2013). Treatment of HCV infection by targeting microRNA. N Engl J Med, 368(18), 1685–1694. https://doi.org/10.1056/NEJMoa1209026
Janssen, Harry L. A., Hendrik W. Reesink, Eric J. Lawitz, Stefan Zeuzem, Maribel Rodriguez-Torres, Keyur Patel, Adriaan J. van der Meer, et al. “Treatment of HCV infection by targeting microRNA.N Engl J Med 368, no. 18 (May 2, 2013): 1685–94. https://doi.org/10.1056/NEJMoa1209026.
Janssen HLA, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013 May 2;368(18):1685–94.
Janssen, Harry L. A., et al. “Treatment of HCV infection by targeting microRNA.N Engl J Med, vol. 368, no. 18, May 2013, pp. 1685–94. Pubmed, doi:10.1056/NEJMoa1209026.
Janssen HLA, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges MR. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013 May 2;368(18):1685–1694.

Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

May 2, 2013

Volume

368

Issue

18

Start / End Page

1685 / 1694

Location

United States

Related Subject Headings

  • RNA, Viral
  • Oligonucleotides
  • Mutation
  • Middle Aged
  • MicroRNAs
  • Male
  • Injections, Subcutaneous
  • Humans
  • Hepatitis C, Chronic
  • Hepacivirus