慢性丙型肝炎病毒感染灵长类动物中 microRNA-122 的治疗性沉默。
Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection.
机构信息
Department of Virology and Immunology and Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA.
出版信息
Science. 2010 Jan 8;327(5962):198-201. doi: 10.1126/science.1178178. Epub 2009 Dec 3.
Abstract
The liver-expressed microRNA-122 (miR-122) is essential for hepatitis C virus (HCV) RNA accumulation in cultured liver cells, but its potential as a target for antiviral intervention has not been assessed. We found that treatment of chronically infected chimpanzees with a locked nucleic acid (LNA)-modified oligonucleotide (SPC3649) complementary to miR-122 leads to long-lasting suppression of HCV viremia, with no evidence of viral resistance or side effects in the treated animals. Furthermore, transcriptome and histological analyses of liver biopsies demonstrated derepression of target mRNAs with miR-122 seed sites, down-regulation of interferon-regulated genes, and improvement of HCV-induced liver pathology. The prolonged virological response to SPC3649 treatment without HCV rebound holds promise of a new antiviral therapy with a high barrier to resistance.
摘要
肝表达的 microRNA-122（miR-122）对于培养的肝细胞中丙型肝炎病毒（HCV）RNA 的积累至关重要，但作为抗病毒干预的靶点尚未得到评估。我们发现，用与 miR-122 互补的锁核酸（LNA）修饰的寡核苷酸（SPC3649）治疗慢性感染的黑猩猩，可导致 HCV 病毒血症的长期抑制，而在治疗动物中没有发现病毒耐药性或副作用的证据。此外，对肝活检组织的转录组和组织学分析表明，miR-122 种子部位的靶 mRNA 去抑制、干扰素调节基因下调，以及改善 HCV 诱导的肝病理。SPC3649 治疗的持久病毒学反应而没有 HCV 反弹，有望成为一种具有高耐药屏障的新抗病毒治疗方法。
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