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MicroRNA-targeting therapeutics for hepatitis C

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Abstract

MiR-122 is a liver-specific microRNA (miRNA) that plays a pivotal role in regulating hepatic functions such as lipid metabolism and stress response. The observation that hepatitis C virus (HCV) could only replicate in miR-122-positive hepatocytes led to the discovery that miR-122 is essential for HCV replication, and miR-122 is now one of the crucial host factors for anti-HCV therapy. Currently, the most advanced miR-122 targeting therapy is SPC3649 (miravirsen), a locked nucleic acid-modified oligonucleotide antagonizing miR-122. This review serves to provide information on the discovery and development of SPC3649, the first miRNA-targeted drug to enter human clinical trials, and introduce other miR-122-targeting therapeutics being developed for hepatitis C.

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References

  • Bartel, D.P. 2009. MicroRNAs: target recognition and regulatory functions. Cell 136: 215–233.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bushati, N., and S.M. Cohen. 2007. microRNA functions. Annual Review of Cell and Developmental Biology 23: 175–205.

    Article  CAS  PubMed  Google Scholar 

  • Chang, J., E. Nicolas, D. Marks, C. Sander, A. Lerro, M.A. Buendia, C. Xu, W.S. Mason, T. Moloshok, R. Bort, K.S. Zaret, and J.M. Taylor. 2004. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biology 1: 106–113.

    Article  CAS  PubMed  Google Scholar 

  • Chang, T.C., and J.T. Mendell. 2007. microRNAs in vertebrate physiology and human disease. Annual Review of Genomics and Human Genetics 8: 215–239.

    Article  CAS  PubMed  Google Scholar 

  • Cooper, C., E.J. Lawitz, P. Ghali, M. Rodriguez-Torres, F.H. Anderson, S.S. Lee, J. Bédard, N. Chauret, R. Thibert, I. Boivin, O. Nicolas, and L. Proulx. 2009. Evaluation of VCH-759 monotherapy in hepatitis C infection. Journal of Hepatology 51: 39–46.

    Article  CAS  PubMed  Google Scholar 

  • Corouge, M., and S. Pol. 2011. New treatments for chronic hepatitis C virus infection. Médecine et maladies infectieuses 41: 579–587.

    Article  CAS  PubMed  Google Scholar 

  • Elmen, J., M. Lindow, S. Schutz, M. Lawrence, A. Petri, S. Obad, M. Lindholm, M. Hedtjarn, H.F. Hansen, U. Berger, S. Gullans, P. Kearney, P. Sarnow, E.M. Straarup, and S. Kauppinen. 2008a. LNA-mediated microRNA silencing in non-human primates. Nature 452: 896–899.

    Article  CAS  PubMed  Google Scholar 

  • Elmen, J., M. Lindow, A. Silahtaroglu, M. Bak, M. Christensen, A. Lind-Thomsen, M. Hedtjarn, J.B. Hansen, H.F. Hansen, E.M. Straarup, K. Mccullagh, P. Kearney, and S. Kauppinen. 2008b. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Research 36: 1153–1162.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Esau, C., S. Davis, S.F. Murray, X.X. Yu, S.K. Pandey, M. Pear, L. Watts, S.L. Booten, M. Graham, R. Mckay, A. Subramaniam, S. Propp, B.A. Lollo, S. Freier, C.F. Bennett, S. Bhanot, and B.P. Monia. 2006. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metabolism 3: 87–98.

    Article  CAS  PubMed  Google Scholar 

  • Gebert, L. F., Rebhan, M. A., Crivelli, S. E., Denzler, R., Stoffel, M., and Hall, J. Miravirsen (SPC3649) can inhibit the biogenesis of miR-122. Nucleic Acids Res, (2013).

  • Hildebrandt-Eriksen, E.S., V. Aarup, R. Persson, H.F. Hansen, M.E. Munk, and H. Orum. 2012. A locked nucleic acid oligonucleotide targeting microRNA 122 is well-tolerated in cynomolgus monkeys. Nucleic Acid Therapeutics 22: 152–161.

    CAS  PubMed  Google Scholar 

  • Janssen, H.L., H.W. Reesink, E.J. Lawitz, S. Zeuzem, M. Rodriguez-Torres, K. Patel, A.J. Van Der Meer, A.K. Patick, A. Chen, Y. Zhou, R. Persson, B.D. King, S. Kauppinen, A.A. Levin, and M.R. Hodges. 2013. Treatment of HCV infection by targeting microRNA. New England Journal of Medicine 368: 1685–1694.

    Article  CAS  PubMed  Google Scholar 

  • Jopling, C.L. 2008. Regulation of hepatitis C virus by microRNA-122. Biochemical Society Transactions 36: 1220–1223.

    Article  CAS  PubMed  Google Scholar 

  • Krutzfeldt, J., N. Rajewsky, R. Braich, K.G. Rajeev, T. Tuschl, M. Manoharan, and M. Stoffel. 2005. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438: 685–689.

    Article  PubMed  Google Scholar 

  • Lagos-Quintana, M., R. Rauhut, A. Yalcin, J. Meyer, W. Lendeckel, and T. Tuschl. 2002. Identification of tissue-specific microRNAs from mouse. Current Biology 12: 735–739.

    Article  CAS  PubMed  Google Scholar 

  • Lanford, R.E., E.S. Hildebrandt-Eriksen, A. Petri, R. Persson, M. Lindow, M.E. Munk, S. Kauppinen, and H. Orum. 2010. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327: 198–201.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liang, T.J., and M.G. Ghany. 2013. Current and future therapies for hepatitis C virus infection. New England Journal of Medicine 368: 1907–1917.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lindow, M., and S. Kauppinen. 2012. Discovering the first microRNA-targeted drug. Journal of Cell Biology 199: 407–412.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nie, W., J. Chen, and Q. Xiu. 2012. Cytotoxic T-lymphocyte associated antigen 4 polymorphisms and asthma risk: a meta-analysis. PLoS One 7: e42062.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pedersen, I.M., G. Cheng, S. Wieland, S. Volinia, C.M. Croce, F.V. Chisari, and M. David. 2007. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449: 919–922.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Poordad, F., J. Mccone, B.R. Bacon, S. Bruno, M.P. Manns, M.S. Sulkowski, I.M. Jacobson, K.R. Reddy, Z.D. Goodman, N. Boparai, M.J. Dinubile, V. Sniukiene, C.A. Brass, J.K. Albrecht, J.P. Bronowicki, and S. Investigators. 2011. Boceprevir for untreated chronic HCV genotype 1 infection. New England Journal of Medicine 364: 1195–1206.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sherman, K.E., S.L. Flamm, N.H. Afdhal, D.R. Nelson, M.S. Sulkowski, G.T. Everson, M.W. Fried, M. Adler, H.W. Reesink, M. Martin, A.J. Sankoh, N. Adda, R.S. Kauffman, S. George, C.I. Wright, F. Poordad, and I.S. Team. 2011. Response-guided telaprevir combination treatment for hepatitis C virus infection. New England Journal of Medicine 365: 1014–1024.

    Article  CAS  PubMed  Google Scholar 

  • Shrivastava, S., A. Mukherjee, and R.B. Ray. 2013. Hepatitis C virus infection, microRNA and liver disease progression. World J Hepatology 5: 479–486.

    Article  Google Scholar 

  • Thomas, D.L. 2013. Global control of hepatitis C: where challenge meets opportunity. Nature Medicine 19: 850–858.

    Article  CAS  PubMed  Google Scholar 

  • Young, D.D., C.M. Connelly, C. Grohmann, and A. Deiters. 2010. Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. Journal of the American Chemical Society 132: 7976–7981.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Chung-Ang University Excellent Student Scholarship in 2012 and by the National Research Foundation (NRF), funded by the Ministry of Science, ICT, and Future Planning [NRF-2013R1A1A3005097 to H.M.].

Conflict of interest

The authors have no conflict of interest in our manuscript.

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Authors and Affiliations

  1. College of Pharmacy, Chung-Ang University, 84 Heukseokro, Dongjakgu, Seoul, 156-756, Korea

    Jihae Baek, Soowon Kang & Hyeyoung Min

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  1. Jihae Baek
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  2. Soowon Kang
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Correspondence to Hyeyoung Min.

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Baek, J., Kang, S. & Min, H. MicroRNA-targeting therapeutics for hepatitis C. Arch. Pharm. Res. 37, 299–305 (2014). https://doi.org/10.1007/s12272-013-0318-9

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  • DOI: https://doi.org/10.1007/s12272-013-0318-9

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