Therapeutic targeting of microRNAs: current status and future challenges (original) (raw)

• Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).
  Article CAS PubMed Google Scholar
• Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).
  CAS PubMed Google Scholar
• Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
  CAS PubMed Google Scholar
• Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004).
  CAS PubMed Google Scholar
• Klattenhoff, C. & Theurkauf, W. Biogenesis and germline functions of piRNAs. Development 135, 3–9 (2008).
  CAS PubMed Google Scholar
• Ghildiyal, M. et al. Endogenous siRNAs derived from transposons and mRNAs in Drosophila somatic cells. Science 320, 1077–1081 (2008).
  CAS PubMed PubMed Central Google Scholar
• Calin, G. A. et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc. Natl Acad. Sci. USA 101, 11755–11760 (2004).
  CAS PubMed PubMed Central Google Scholar
• Calin, G. A. et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl Acad. Sci. USA 101, 2999–3004 (2004).
  CAS PubMed PubMed Central Google Scholar
• Farazi, T. A., Spitzer, J. I., Morozov, P. & Tuschl, T. miRNAs in human cancer. J. Pathol. 223, 102–115 (2011).
  CAS PubMed Google Scholar
• van Rooij, E. & Olson, E. N. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nature Rev. Drug Discov. 11, 860–872 (2012).
  CAS Google Scholar
• O'Connell, R. M., Rao, D. S., Chaudhuri, A. A. & Baltimore, D. Physiological and pathological roles for microRNAs in the immune system. Nature Rev. Immunol. 10, 111–122 (2010).
  CAS Google Scholar
• Esau, C. C. Inhibition of microRNA with antisense oligonucleotides. Methods 44, 55–60 (2008).
  CAS PubMed Google Scholar
• Lennox, K. A. & Behlke, M. A. Chemical modification and design of anti-miRNA oligonucleotides. Gene Ther. 18, 1111–1120 (2011).
  CAS PubMed Google Scholar
• Bumcrot, D., Manoharan, M., Koteliansky, V. & Sah, D. W. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nature Chem. Biol. 2, 711–719 (2006).
  CAS Google Scholar
• Lanford, R. E. et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327, 198–201 (2010).
  CAS PubMed Google Scholar
• Krutzfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).
  PubMed Google Scholar
• Elmen, J. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452, 896–899 (2008).
  CAS PubMed Google Scholar
• Li, Z. & Rana, T. M. Molecular mechanisms of RNA-triggered gene silencing machineries. Accounts Chem. Res. 45, 1122–1131 (2012).
  CAS Google Scholar
• Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nature Rev. Genet. 11, 597–610 (2010).
  CAS PubMed Google Scholar
• Han, J. et al. Posttranscriptional crossregulation between Drosha and DGCR8. Cell 136, 75–84 (2009).
  CAS PubMed PubMed Central Google Scholar
• Triboulet, R., Chang, H. M., Lapierre, R. J. & Gregory, R. I. Post-transcriptional control of DGCR8 expression by the microprocessor. RNA 15, 1005–1011 (2009).
  CAS PubMed PubMed Central Google Scholar
• Gregory, R. I. et al. The microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).
  CAS PubMed Google Scholar
• Chendrimada, T. P. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436, 740–744 (2005).
  CAS PubMed PubMed Central Google Scholar
• Melo, S. A. et al. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nature Genet. 41, 365–370 (2009).
  CAS PubMed Google Scholar
• Paroo, Z., Ye, X., Chen, S. & Liu, Q. Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling. Cell 139, 112–122 (2009).
  CAS PubMed PubMed Central Google Scholar
• Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).
  CAS PubMed Google Scholar
• Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).
  CAS PubMed Google Scholar
• Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855–862 (1993).
  CAS PubMed Google Scholar
• Pillai, R. S. et al. Inhibition of translational initiation by Let-7 microRNA in human cells. Science 309, 1573–1576 (2005).
  CAS PubMed Google Scholar
• Olsen, P. H. & Ambros, V. The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. Dev. Biol. 216, 671–680 (1999).
  CAS PubMed Google Scholar
• Petersen, C. P., Bordeleau, M. E., Pelletier, J. & Sharp, P. A. Short RNAs repress translation after initiation in mammalian cells. Mol. Cell 21, 533–542 (2006).
  CAS PubMed Google Scholar
• Lytle, J. R., Yario, T. A. & Steitz, J. A. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc. Natl Acad. Sci. USA 104, 9667–9672 (2007).
  CAS PubMed PubMed Central Google Scholar
• Bagga, S. et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122, 553–563 (2005).
  CAS PubMed Google Scholar
• Guo, H., Ingolia, N. T., Weissman, J. S. & Bartel, D. P. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466, 835–840 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, J. et al. A role for the P-body component GW182 in microRNA function. Nature Cell Biol. 7, 1261–1266 (2005).
  PubMed Google Scholar
• Eulalio, A., Huntzinger, E. & Izaurralde, E. GW182 interaction with Argonaute is essential for miRNA-mediated translational repression and mRNA decay. Nature Struct. Mol. Biol. 15, 346–353 (2008).
  CAS Google Scholar
• Behm-Ansmant, I. et al. mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev. 20, 1885–1898 (2006).
  CAS PubMed PubMed Central Google Scholar
• Chu, C. Y. & Rana, T. M. Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biol. 4, e210 (2006).
  PubMed PubMed Central Google Scholar
• Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).
  CAS PubMed PubMed Central Google Scholar
• Stark, A., Brennecke, J., Russell, R. B. & Cohen, S. M. Identification of Drosophila microRNA targets. PLoS Biol. 1, E60 (2003).
  PubMed PubMed Central Google Scholar
• Grun, D., Wang, Y. L., Langenberger, D., Gunsalus, K. C. & Rajewsky, N. microRNA target predictions across seven Drosophila species and comparison to mammalian targets. PLoS Comput. Biol. 1, e13 (2005).
  PubMed PubMed Central Google Scholar
• Gaidatzis, D., van Nimwegen, E., Hausser, J. & Zavolan, M. Inference of miRNA targets using evolutionary conservation and pathway analysis. BMC Bioinformatics 8, 69 (2007).
  PubMed PubMed Central Google Scholar
• Ma, L. et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nature Cell Biol. 12, 247–256 (2010).
  CAS PubMed Google Scholar
• Li, Z., Yang, C. S., Nakashima, K. & Rana, T. M. Small RNA-mediated regulation of iPS cell generation. EMBO J. 30, 823–834 (2011).
  PubMed PubMed Central Google Scholar
• Papagiannakopoulos, T., Shapiro, A. & Kosik, K. S. MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 68, 8164–8172 (2008).
  CAS PubMed Google Scholar
• Johnson, C. D. et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res. 67, 7713–7722 (2007).
  CAS PubMed Google Scholar
• Ebert, M. S., Neilson, J. R. & Sharp, P. A. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nature Methods 4, 721–726 (2007).
  CAS PubMed Google Scholar
• Ebert, M. S. & Sharp, P. A. MicroRNA sponges: progress and possibilities. RNA 16, 2043–2050 (2010).
  CAS PubMed PubMed Central Google Scholar
• Tay, Y. et al. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147, 344–357 (2011).
  CAS PubMed PubMed Central Google Scholar
• Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).
  CAS PubMed PubMed Central Google Scholar
• Karreth, F. A. et al. In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 147, 382–395 (2011).
  CAS PubMed PubMed Central Google Scholar
• Gumireddy, K. et al. Small-molecule inhibitors of microRNA miR-21 function. Angew. Chem. Int. Ed. Engl. 47, 7482–7484 (2008).
  CAS PubMed PubMed Central Google Scholar
• Young, D. D., Connelly, C. M., Grohmann, C. & Deiters, A. Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. J. Am. Chem. Soc. 132, 7976–7981 (2010).
  CAS PubMed Google Scholar
• Boutla, A., Delidakis, C. & Tabler, M. Developmental defects by antisense-mediated inactivation of micro-RNAs 2 and 13 in Drosophila and the identification of putative target genes. Nucleic Acids Res. 31, 4973–4980 (2003).
  CAS PubMed PubMed Central Google Scholar
• Lamond, A. I. & Sproat, B. S. Antisense oligonucleotides made of 2′-_O_-alkylRNA: their properties and applications in RNA biochemistry. FEBS Lett. 325, 123–127 (1993).
  CAS PubMed Google Scholar
• Verma, S. & Eckstein, F. Modified oligonucleotides: synthesis and strategy for users. Annu. Rev. Biochem. 67, 99–134 (1998).
  CAS PubMed Google Scholar
• Cummins, L. L. et al. Characterization of fully 2′-modified oligoribonucleotide hetero- and homoduplex hybridization and nuclease sensitivity. Nucleic Acids Res. 23, 2019–2024 (1995).
  CAS PubMed PubMed Central Google Scholar
• Majlessi, M., Nelson, N. C. & Becker, M. M. Advantages of 2′-_O_-methyl oligoribonucleotide probes for detecting RNA targets. Nucleic Acids Res. 26, 2224–2229 (1998).
  CAS PubMed PubMed Central Google Scholar
• Hutvagner, G., Simard, M. J., Mello, C. C. & Zamore, P. D. Sequence-specific inhibition of small RNA function. PLoS Biol. 2, E98 (2004).
  PubMed PubMed Central Google Scholar
• Meister, G., Landthaler, M., Dorsett, Y. & Tuschl, T. Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 10, 544–550 (2004).
  CAS PubMed PubMed Central Google Scholar
• Lennox, K. A. & Behlke, M. A. A direct comparison of anti-microRNA oligonucleotide potency. Pharm. Res. 27, 1788–1799 (2010).
  CAS PubMed Google Scholar
• Geary, R. S. Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin. Drug Metab. Toxicol. 5, 381–391 (2009).
  CAS PubMed Google Scholar
• Chiu, Y. L. & Rana, T. M. RNAi in human cells: basic structural and functional features of small interfering RNA. Mol. Cell 10, 549–561 (2002).
  CAS PubMed Google Scholar
• Chiu, Y. L. & Rana, T. M. siRNA function in RNAi: a chemical modification analysis. RNA 9, 1034–1048 (2003).
  CAS PubMed PubMed Central Google Scholar
• Soutschek, J. et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173–178 (2004).
  CAS PubMed Google Scholar
• Yu, D. et al. Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell 150, 895–908 (2012).
  CAS PubMed PubMed Central Google Scholar
• Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).
  CAS PubMed Google Scholar
• Ma, L. et al. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nature Biotech. 28, 341–347 (2010).
  CAS Google Scholar
• Manoharan, M. 2′-carbohydrate modifications in antisense oligonucleotide therapy: importance of conformation, configuration and conjugation. Biochim. Biophys. Acta 1489, 117–130 (1999).
  CAS PubMed Google Scholar
• Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell. Metab. 3, 87–98 (2006).
  CAS PubMed Google Scholar
• Kawasaki, A. M. et al. Uniformly modified 2′-deoxy-2′-fluoro phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets. J. Med. Chem. 36, 831–841 (1993).
  CAS PubMed Google Scholar
• Davis, S., Lollo, B., Freier, S. & Esau, C. Improved targeting of miRNA with antisense oligonucleotides. Nucleic Acids Res. 34, 2294–2304 (2006).
  CAS PubMed PubMed Central Google Scholar
• Rigo, F. et al. Synthetic oligonucleotides recruit ILF2/3 to RNA transcripts to modulate splicing. Nature Chem. Biol. 8, 555–561 (2012).
  CAS Google Scholar
• Petersen, M., Bondensgaard, K., Wengel, J. & Jacobsen, J. P. Locked nucleic acid (LNA) recognition of RNA: NMR solution structures of LNA:RNA hybrids. J. Am. Chem. Soc. 124, 5974–5982 (2002).
  CAS PubMed Google Scholar
• Singh, K. S., Koshkin, A. A., Wengel, J. & Nielsen, P. LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition. Chem. Comm. 1998, 455–456 (1998).
  Google Scholar
• Chan, J. A., Krichevsky, A. M. & Kosik, K. S. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65, 6029–6033 (2005).
  CAS PubMed Google Scholar
• Orom, U. A., Kauppinen, S. & Lund, A. H. LNA-modified oligonucleotides mediate specific inhibition of microRNA function. Gene 372, 137–141 (2006).
  CAS PubMed Google Scholar
• Koshkin, A. A. et al. LNA (locked nucleic acid): an RNA mimic forming exceedingly stable LNA:LNA duplexes. J. Am. Chem. Soc. 120, 13252–13253 (1998).
  CAS Google Scholar
• Elmen, J. et al. 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 Res. 36, 1153–1162 (2008).
  CAS PubMed Google Scholar
• Obad, S. et al. Silencing of microRNA families by seed-targeting tiny LNAs. Nature Genet. 43, 371–378 (2011).
  CAS PubMed Google Scholar
• Lennox, K. A., Owczarzy, R., Thomas, D. M., Walder, J. A. & Behlke, M. A. Improved performance of anti-miRNA oligonucleotides using a novel non-nucleotide modifier. Mol. Ther. Nucleic Acids 2, e117 (2013).
  PubMed PubMed Central Google Scholar
• Wolfrum, C. et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nature Biotech. 25, 1149–1157 (2007).
  CAS Google Scholar
• Nishina, K. et al. Efficient in vivo delivery of siRNA to the liver by conjugation of alpha-tocopherol. Mol. Ther. 16, 734–740 (2008).
  CAS PubMed Google Scholar
• Kortylewski, M. et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nature Biotech. 27, 925–932 (2009).
  CAS Google Scholar
• Hsu, T. & Mitragotri, S. Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Proc. Natl Acad. Sci. USA 108, 15816–15821 (2011).
  CAS PubMed PubMed Central Google Scholar
• Morrissey, D. V. et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nature Biotech. 23, 1002–1007 (2005).
  CAS Google Scholar
• Morrissey, D. V. et al. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology 41, 1349–1356 (2005).
  CAS PubMed Google Scholar
• Zimmermann, T. S. et al. RNAi-mediated gene silencing in non-human primates. Nature 441, 111–114 (2006).
  CAS PubMed Google Scholar
• Akinc, A. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nature Biotech. 26, 561–569 (2008).
  CAS Google Scholar
• Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).
  CAS PubMed PubMed Central Google Scholar
• Peer, D., Park, E. J., Morishita, Y., Carman, C. V. & Shimaoka, M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science 319, 627–630 (2008).
  CAS PubMed PubMed Central Google Scholar
• Palliser, D. et al. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature 439, 89–94 (2006).
  CAS PubMed Google Scholar
• Kumar, P., Lee, S. K., Shankar, P. & Manjunath, N. A single siRNA suppresses fatal encephalitis induced by two different flaviviruses. PLoS Med. 3, e96 (2006).
  PubMed PubMed Central Google Scholar
• Malam, Y., Loizidou, M. & Seifalian, A. M. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol. Sci. 30, 592–599 (2009).
  CAS PubMed Google Scholar
• Davis, M. E., Chen, Z. G. & Shin, D. M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Rev. Drug Discov. 7, 771–782 (2008).
  CAS Google Scholar
• Schiffelers, R. M. et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 32, e149 (2004).
  PubMed PubMed Central Google Scholar
• Heidel, J. D. et al. Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA. Proc. Natl Acad. Sci. USA 104, 5715–5721 (2007).
  CAS PubMed PubMed Central Google Scholar
• Hu-Lieskovan, S., Heidel, J. D., Bartlett, D. W., Davis, M. E. & Triche, T. J. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. Cancer Res. 65, 8984–8992 (2005).
  CAS PubMed Google Scholar
• Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010).
  CAS PubMed PubMed Central Google Scholar
• Baigude, H., McCarroll, J., Yang, C. S., Swain, P. M. & Rana, T. M. Design and creation of new nanomaterials for therapeutic RNAi. ACS Chem. Biol. 2, 237–241 (2007).
  CAS PubMed Google Scholar
• Su, J., Baigude, H., McCarroll, J. & Rana, T. M. Silencing microRNA by interfering nanoparticles in mice. Nucleic Acids Res. 39, e38 (2011).
  CAS PubMed PubMed Central Google Scholar
• Lee, H. et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nature Nanotech. 7, 389–393 (2012).
  CAS Google Scholar
• Song, E. et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nature Biotech. 23, 709–717 (2005).
  CAS Google Scholar
• Kumar, P. et al. T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 134, 577–586 (2008).
  CAS PubMed PubMed Central Google Scholar
• Wen, W. H. et al. Targeted inhibition of HBV gene expression by single-chain antibody mediated small interfering RNA delivery. Hepatology 46, 84–94 (2007).
  CAS PubMed Google Scholar
• Yao, Y. D. et al. Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis. Sci. Transl. Med. 4, 130ra148 (2012).
  Google Scholar
• Lal, A. et al. miR-24 inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to “seedless” 3′UTR microRNA recognition elements. Mol. Cell 35, 610–625 (2009).
  CAS PubMed PubMed Central Google Scholar
• Kloosterman, W. P., Lagendijk, A. K., Ketting, R. F., Moulton, J. D. & Plasterk, R. H. Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development. PLoS Biol. 5, e203 (2007).
  PubMed PubMed Central Google Scholar
• van Deutekom, J. C. et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N. Engl. J. Med. 357, 2677–2686 (2007).
  CAS PubMed Google Scholar
• Hammond, S. M. & Wood, M. J. PRO-051, an antisense oligonucleotide for the potential treatment of Duchenne muscular dystrophy. Curr. Opin. Mol. Ther. 12, 478–486 (2010).
  CAS PubMed Google Scholar
• Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunol. 11, 373–384 (2010).
  CAS Google Scholar
• Kariko, K., Bhuyan, P., Capodici, J. & Weissman, D. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J. Immunol. 172, 6545–6549 (2004).
  CAS PubMed Google Scholar
• Kleinman, M. E. et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452, 591–597 (2008).
  CAS PubMed PubMed Central Google Scholar
• Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).
  CAS PubMed Google Scholar
• Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).
  CAS PubMed Google Scholar
• Judge, A. D. et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nature Biotech. 23, 457–462 (2005).
  CAS Google Scholar
• Hornung, V. et al. Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nature Med. 11, 263–270 (2005).
  CAS PubMed Google Scholar
• Jurk, M. et al. Immunostimulatory potential of silencing RNAs can be mediated by a non-uridine-rich Toll-like receptor 7 motif. Nucleic Acid. Ther. 21, 201–214 (2011).
  CAS PubMed Google Scholar
• Bennett, C. F. & Swayze, E. E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 50, 259–293 (2010).
  CAS PubMed Google Scholar
• Henry, S. P., Novotny, W., Leeds, J., Auletta, C. & Kornbrust, D. J. Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense Nucleic Acid Drug Dev. 7, 503–510 (1997).
  CAS PubMed Google Scholar
• Galbraith, W. M., Hobson, W. C., Giclas, P. C., Schechter, P. J. & Agrawal, S. Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res. Dev. 4, 201–206 (1994).
  CAS PubMed Google Scholar
• Hildebrandt-Eriksen, E. S. et al. A locked nucleic acid oligonucleotide targeting microRNA 122 is well-tolerated in cynomolgus monkeys. Nucleic Acid Ther. 22, 152–161 (2012).
  CAS PubMed Google Scholar
• Swayze, E. E. et al. Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals. Nucleic Acids Res. 35, 687–700 (2007).
  CAS PubMed Google Scholar
• Stanton, R. et al. Chemical modification study of antisense gapmers. Nucleic Acid. Ther. 22, 344–359 (2012).
  CAS PubMed Google Scholar
• Kakiuchi-Kiyota, S. et al. Comparison of hepatic transcription profiles of locked ribonucleic acid (LNA) antisense oligonucleotides: evidence of distinct pathways contributing to non-target mediated toxicity in mice. Toxicol. Sci. 138, 234–248 (2013).
  PubMed Google Scholar
• Garzon, R., Marcucci, G. & Croce, C. M. Targeting microRNAs in cancer: rationale, strategies and challenges. Nature Rev. Drug Discov. 9, 775–789 (2010).
  CAS Google Scholar
• Matsubara, H. et al. Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92. Oncogene 26, 6099–6105 (2007).
  CAS PubMed Google Scholar
• Ventura, A. et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132, 875–886 (2008).
  CAS PubMed PubMed Central Google Scholar
• Kang, S. G. et al. MicroRNAs of the miR-17 approximately 92 family are critical regulators of TFH differentiation. Nature Immunol. 14, 849–857 (2013).
  CAS Google Scholar
• Brannon-Peppas, L. & Blanchette, J. O. Nanoparticle and targeted systems for cancer therapy. Adv. Drug Deliv. Rev. 64, S206–S212 (2012).
  Google Scholar
• Brigger, I., Dubernet, C. & Couvreur, P. Nanoparticles in cancer therapy and diagnosis. Adv. Drug Deliv. Rev. 64, S24–S36 (2012).
  Google Scholar
• Jain, R. K. Delivery of molecular and cellular medicine to solid tumors. Adv. Drug. Deliv. Rev. 64, S353–S365 (2012).
  Google Scholar
• Gilleron, J. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nature Biotech. 31, 638–646 (2013).
  CAS Google Scholar
• Jopling, C. L., Yi, M., Lancaster, A. M., Lemon, S. M. & Sarnow, P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309, 1577–1581 (2005).
  CAS PubMed Google Scholar
• Lindow, M. & Kauppinen, S. Discovering the first microRNA-targeted drug. J. Cell Biol. 199, 407–412 (2012).
  CAS PubMed PubMed Central Google Scholar
• Iorio, M. V. & Croce, C. M. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol. Med. 4, 143–159 (2012).
  CAS PubMed PubMed Central Google Scholar
• Bouchie, A. First microRNA mimic enters clinic. Nature Biotech. 31, 577–577 (2013).
  CAS Google Scholar
• Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).
  CAS PubMed Google Scholar
• Takamizawa, J. et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64, 3753–3756 (2004).
  CAS PubMed Google Scholar
• Johnson, S. M. et al. RAS is regulated by the let-7 microRNA family. Cell 120, 635–647 (2005).
  CAS PubMed Google Scholar
• Mayr, C., Hemann, M. T. & Bartel, D. P. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315, 1576–1579 (2007).
  CAS PubMed PubMed Central Google Scholar
• Kumar, M. S. et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc. Natl Acad. Sci. USA 105, 3903–3908 (2008).
  CAS PubMed PubMed Central Google Scholar
• Esquela-Kerscher, A. et al. The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 7, 759–764 (2008).
  CAS PubMed Google Scholar
• Yu, F. et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).
  CAS PubMed Google Scholar
• Volinia, S. et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA 103, 2257–2261 (2006).
  CAS PubMed PubMed Central Google Scholar
• Croce, C. M. Causes and consequences of microRNA dysregulation in cancer. Nature Rev. Genet. 10, 704–714 (2009).
  CAS PubMed Google Scholar
• Meng, F. et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133, 647–658 (2007).
  CAS PubMed Google Scholar
• Zhu, S., Si, M. L., Wu, H. & Mo, Y. Y. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J. Biol. Chem. 282, 14328–14336 (2007).
  CAS PubMed Google Scholar
• Asangani, I. A. et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27, 2128–2136 (2008).
  CAS PubMed Google Scholar
• Frankel, L. B. et al. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J. Biol. Chem. 283, 1026–1033 (2008).
  CAS PubMed Google Scholar
• Chau, B. N. et al. MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci. Transl. Med. 4, 121ra118 (2012).
  Google Scholar
• van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).
  CAS PubMed Google Scholar
• Montgomery, R. L. et al. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124, 1537–1547 (2011).
  CAS PubMed PubMed Central Google Scholar
• Porrello, E. R. et al. miR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ. Res. 109, 670–679 (2011).
  CAS PubMed PubMed Central Google Scholar
• Hullinger, T. G. et al. Inhibition of miR-15 protects against cardiac ischemic injury. Circ. Res. 110, 71–81 (2012).
  CAS PubMed Google Scholar
• Porrello, E. R. et al. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc. Natl Acad. Sci. USA 110, 187–192 (2013).
  CAS PubMed Google Scholar
• Fornari, F. et al. miR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 27, 5651–5661 (2008).
  CAS PubMed Google Scholar
• Gramantieri, L. et al. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin. Cancer Res. 15, 5073–5081 (2009).
  CAS PubMed PubMed Central Google Scholar
• Pineau, P. et al. miR-221 overexpression contributes to liver tumorigenesis. Proc. Natl Acad. Sci. USA 107, 264–269 (2010).
  CAS PubMed Google Scholar
• Park, J. K. et al. miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 71, 7608–7616 (2011).
  CAS PubMed PubMed Central Google Scholar
• Trajkovski, M. et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011).
  CAS PubMed Google Scholar
• Khraiwesh, B. et al. Transcriptional control of gene expression by microRNAs. Cell 140, 111–122 (2010).
  CAS PubMed Google Scholar
• Eiring, A. M. et al. miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell 140, 652–665 (2010).
  CAS PubMed PubMed Central Google Scholar
• Braconi, C. et al. microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene 30, 4750–4756 (2011).
  CAS PubMed PubMed Central Google Scholar
• Taulli, R., Loretelli, C. & Pandolfi, P. P. From pseudo-ceRNAs to circ-ceRNAs: a tale of cross-talk and competition. Nature Struct. Mol. Biol. 20, 541–543 (2013).
  CAS Google Scholar
• Zisoulis, D. G., Kai, Z. S., Chang, R. K. & Pasquinelli, A. E. Autoregulation of microRNA biogenesis by let-7 and Argonaute. Nature 486, 541–544 (2012).
  CAS PubMed PubMed Central Google Scholar
• Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).
  CAS PubMed PubMed Central Google Scholar
• Tang, X., Li, M., Tucker, L. & Ramratnam, B. Glycogen synthase kinase 3 beta (GSK3β) phosphorylates the RNAase III enzyme Drosha at S300 and S302. PLoS ONE 6, e20391 (2011).
  CAS PubMed PubMed Central Google Scholar
• Wu, C. et al. Hypoxia potentiates microRNA-mediated gene silencing through posttranslational modification of Argonaute2. Mol. Cell. Biol. 31, 4760–4774 (2011).
  CAS PubMed PubMed Central Google Scholar
• Zeng, Y., Sankala, H., Zhang, X. & Graves, P. R. Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies. Biochem. J. 413, 429–436 (2008).
  CAS PubMed Google Scholar
• Heo, I. et al. Lin28 mediates the terminal uridylation of let-7 precursor microRNA. Mol. Cell 32, 276–284 (2008).
  CAS PubMed Google Scholar