title: Treatment of HCV infection by targeting microRNA.
abstract: 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.).
authors.affiliation: Erasmus MC University Hospital, Rotterdam, The Netherlands. harry.janssen@uhn.ca
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Reesink
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lawitz
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.forename: Keyur
authors.initials: K
authors.lastname: Patel
authors.forename: Adriaan J
authors.initials: AJ
authors.lastname: van der Meer
authors.forename: Amy K
authors.initials: AK
authors.lastname: Patick
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Robert
authors.initials: R
authors.lastname: Persson
authors.forename: Barney D
authors.initials: BD
authors.lastname: King
authors.forename: Sakari
authors.initials: S
authors.lastname: Kauppinen
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Levin
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hodges
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001665:Binding Sites / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009841:Oligonucleotides / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood
chemical_list: D000998:Antiviral Agents; D035683:MicroRNAs; D009841:Oligonucleotides; D012367:RNA, Viral; C581159:miravirsen