Ottosen Søren, Parsley Todd B, Yang Lu, Zeh Karin, van Doorn Leen-Jan, van der Veer Eva, Raney Anneke K, Hodges Michael R, Patick Amy K
Santaris Pharma A/S, Hørsholm, Denmark.
ImQuest BioSciences, Frederick, Maryland, USA.
Antimicrob Agents Chemother. 2015 Jan;59(1):599-608. doi: 10.1128/AAC.04220-14. Epub 2014 Nov 10.
Miravirsen is a β-D-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 (EC50) of 0.67 μM. No cytotoxicity was observed up to the highest concentration tested (>320 μM) in different cell culture models, yielding a therapeutic index of ≥ 297. Combination studies of miravirsen with interferon α2b, ribavirin, and nonnucleoside (VX-222) and nucleoside (2'-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' untranslated region (UTR) from cells passaged in the presence of up to 20 μM (40-fold the miravirsen EC50 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'UTR 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).
米拉维林是一种β-D-氧锁定核酸修饰的硫代磷酸反义寡核苷酸，靶向肝脏特异性微小RNA-122（miR-122）。米拉维林对丙型肝炎病毒（HCV）1b型复制子具有抗病毒活性，平均50%有效浓度（EC50）为0.67μM。在不同细胞培养模型中，直至测试的最高浓度（>320μM）均未观察到细胞毒性，治疗指数≥297。米拉维林与干扰素α2b、利巴韦林以及NS5B、NS5A（BMS-790052）或NS3（特拉匹韦）的非核苷（VX-222）和核苷（2'-甲基胞苷）抑制剂的联合研究表明存在相加相互作用。当针对对NS3、NS5A和NS5B抑制剂耐药的HCV复制子进行测试时，米拉维林显示出广泛的抗病毒活性，敏感性降低不到2倍。在连续传代研究中，在传代第72天，在存在高达20μM（米拉维林EC50浓度的40倍）的情况下传代的细胞中，HCV 5'非翻译区（UTR）观察到A4C核苷酸变化，但在早期时间点（传代至39天）未观察到。同样，在米拉维林2期临床试验治疗完成后病毒反弹的受试者的HCV 5'UTR中观察到C3U核苷酸变化。构建包含A4C变化的HCV变体对米拉维林完全敏感。C3U HCV变体对米拉维林的敏感性总体降低，但对所有其他测试的抗HCV药物完全敏感。总之，米拉维林已显示出广泛的抗病毒活性和相对较高的耐药基因屏障。与米拉维林耐药相关的核苷酸变化的鉴定应有助于进一步阐明miR-122与HCV相互作用的生物学机制。（该临床试验研究已在ClinicalTrials.gov上注册，注册号为NCT01200420）
