{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:13:37Z","timestamp":1791278017769,"version":"4.1.0"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2015,1,1]],"date-time":"2015-01-01T00:00:00Z","timestamp":1420070400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Miravirsen is a \u03b2-\n            <jats:sc>d<\/jats:sc>\n            -oxy-locked nucleic acid-modified phosphorothioate antisense oligonucleotide targeting the liver-specific microRNA-122 (miR-122). Miravirsen demonstrated antiviral activity against hepatitis C virus (HCV) genotype 1b replicons with a mean 50% effective concentration (EC\n            <jats:sub>50<\/jats:sub>\n            ) of 0.67 \u03bcM. No cytotoxicity was observed up to the highest concentration tested (&gt;320 \u03bcM) in different cell culture models, yielding a therapeutic index of \u2265297. Combination studies of miravirsen with interferon \u03b12b, ribavirin, and nonnucleoside (VX-222) and nucleoside (2\u2032-methylcytidine) inhibitors of NS5B, NS5A (BMS-790052), or NS3 (telaprevir) indicated additive interactions. Miravirsen demonstrated broad antiviral activity when tested against HCV replicons resistant to NS3, NS5A, and NS5B inhibitors with less than 2-fold reductions in susceptibility. In serial passage studies, an A4C nucleotide change was observed in the HCV 5\u2032 untranslated region (UTR) from cells passaged in the presence of up to 20 \u03bcM (40-fold the miravirsen EC\n            <jats:sub>50<\/jats:sub>\n            concentration) at day 72 of passage but not at earlier time points (up to 39 days of passage). Likewise, a C3U nucleotide change was observed in the HCV 5\u2032UTR from subjects with viral rebound after the completion of therapy in a miravirsen phase 2 clinical trial. An HCV variant constructed to contain the A4C change was fully susceptible to miravirsen. A C3U HCV variant demonstrated overall reductions in susceptibility to miravirsen but was fully susceptible to all other anti-HCV agents tested. In summary, miravirsen has demonstrated broad antiviral activity and a relatively high genetic barrier to resistance. The identification of nucleotide changes associated with miravirsen resistance should help further elucidate the biology of miR-122 interactions with HCV. (The clinical trial study has been registered at ClinicalTrials.gov under registration no. NCT01200420).\n          <\/jats:p>","DOI":"10.1128\/aac.04220-14","type":"journal-article","created":{"date-parts":[[2014,11,11]],"date-time":"2014-11-11T05:42:42Z","timestamp":1415684562000},"page":"599-608","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":232,"title":["<i>In Vitro<\/i>\n            Antiviral Activity and Preclinical and Clinical Resistance Profile of Miravirsen, a Novel Anti-Hepatitis C Virus Therapeutic Targeting the Human Factor miR-122"],"prefix":"10.1128","volume":"59","author":[{"given":"S\u00f8ren","family":"Ottosen","sequence":"first","affiliation":[{"name":"Santaris Pharma A\/S, H\u00f8rsholm, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd B.","family":"Parsley","sequence":"additional","affiliation":[{"name":"ImQuest BioSciences, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Yang","sequence":"additional","affiliation":[{"name":"ImQuest BioSciences, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Zeh","sequence":"additional","affiliation":[{"name":"Santaris Pharma A\/S Corp., San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leen-Jan","family":"van Doorn","sequence":"additional","affiliation":[{"name":"DDL Diagnostic Laboratory, Voorburg, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"van der Veer","sequence":"additional","affiliation":[{"name":"DDL Diagnostic Laboratory, Voorburg, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke K.","family":"Raney","sequence":"additional","affiliation":[{"name":"Santaris Pharma A\/S Corp., San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Hodges","sequence":"additional","affiliation":[{"name":"Santaris Pharma A\/S Corp., San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy K.","family":"Patick","sequence":"additional","affiliation":[{"name":"Santaris Pharma A\/S Corp., San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(05)70216-4"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1104430"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3851\/IMP2127"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2011.01.009"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2010.03430.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00527-13"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2011.12.007"},{"key":"e_1_3_2_9_2","first-page":"237","article-title":"Arrest all accessories\u2013inhibition of hepatitis C virus by compounds that target host factors","volume":"12","author":"von Hahn T","year":"2011","unstructured":"von Hahn T, Ciesek S, Manns MP. 2011. 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