Lanford, RE, Hildebrandt-Eriksen, ES, Petri, A, Persson, R, Lindow, M, Munk, ME et al.. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327: 198-201

Department of Virology and Immunology and Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA.
Science (Impact Factor: 33.61). 12/2009; 327(5962):198-201. DOI: 10.1126/science.1178178
Source: PubMed


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.

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    • "Taken together, these results suggest that miR-122 sponging by HCV can exist in more physiologic miR-122 concentration settings. Figure 4. Meta-Analysis of Published Array Data Suggests HCV-Induced Changes on the miR-122 Target Network (A) Miravirsen pre-and post-treatment array data from four HCV infected chimpanzees (Lanford et al., 2010) was binned according to conserved 7-to 8-mer TargetScan (TS) predictions for miR-15 or miR-122, or from miR-122 targets with CLIP support from the current study. Boxplot whiskers denote 1.5 times the inter-quartile distance from the nearest quartile. "
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    ABSTRACT: Hepatitis C virus (HCV) uniquely requires the liver-specific microRNA-122 for replication, yet global effects on endogenous miRNA targets during infection are unexplored. Here, high-throughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (AGO) during HCV infection showed robust AGO binding on the HCV 5'UTR at known and predicted miR-122 sites. On the human transcriptome, we observed reduced AGO binding and functional mRNA de-repression of miR-122 targets during virus infection. This miR-122 "sponge" effect was relieved and redirected to miR-15 targets by swapping the miRNA tropism of the virus. Single-cell expression data from reporters containing miR-122 sites showed significant de-repression during HCV infection depending on expression level and site number. We describe a quantitative mathematical model of HCV-induced miR-122 sequestration and propose that such miR-122 inhibition by HCV RNA may result in global de-repression of host miR-122 targets, providing an environment fertile for the long-term oncogenic potential of HCV. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 03/2015; 160(6):1099-1110. DOI:10.1016/j.cell.2015.02.025 · 32.24 Impact Factor
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    • "LNA-antimiR/ASOs have high affi nity binding to target miRNAs and lower dose requirements, making it a more biologically effective inhibition strategy. Systemic delivery of unconjugated LNA-antimiR has been shown to signifi cantly silence miR-122 in liver during chronic hepatitis C virus (HCV) infection (Elmén et al., 2008; Lanford et al., 2010). Currently, the fi rst miRNA-targeted drug, antimiR-122 LNA, is under phase II trial to treat and test the safety and tolerability of the drug in chronic HCV infected patients (Stenvang et al., 2012). "

    • "Although miRNA inhibitors are generally water soluble, their size and charge prevent them to be absorbed by the intestine, thus becoming bad candidates for oral therapy. Their long-lasting effects shown in different studies (Krutzfeldt et al. 2005; Elmen et al. 2008; Lanford et al. 2010; Obad et al. 2011; Rayner et al. 2011a, b; van Rooij and Olson 2012) suggest their potential use for chronic rather than acute disease. Whereas under normal unstressed conditions miRNAs only slightly change protein expression (Selbach et al. 2008), pharmacological inhibition under pathological stress conditions may become relevant (Mendell and Olson 2012). "
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    ABSTRACT: The specificity of Watson-Crick base pairing and the development of several chemical modifications to oligonucleotides have enabled the development of novel drug classes for the treatment of different human diseases. This review focuses on promising results of recent preclinical or clinical studies on targeting HDL metabolism and function by antisense oligonucleotides and miRNA-based therapies. Although many hurdles regarding basic mechanism of action, delivery, specificity, and toxicity need to be overcome, promising results from recent clinical trials and recent approval of these types of therapy to treat dyslipidemia suggest that the treatment of HDL dysfunction will benefit from these unique clinical opportunities. Moreover, an overview of monoclonal antibodies (mAbs) developed for the treatment of dyslipidemia and cardiovascular disease and currently being tested in clinical studies is provided. Initial studies have shown that these compounds are generally safe and well tolerated, but ongoing large clinical studies will assess their long-term safety and efficacy.
    Handbook of experimental pharmacology 01/2015; 224:649-89. DOI:10.1007/978-3-319-09665-0_22
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