Use of small RNAs for therapeutic gene silencing: risk versus benefit

Fire, 1998, Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans, Nature, 391, 806, 10.1038/35888 Castanotto, 2009, The promises and pitfalls of RNA-interference-based therapeutics, Nature, 457, 426, 10.1038/nature07758 Kim, 2007, Strategies for silencing human disease using RNA interference, Nat. Rev. Genet., 8, 173, 10.1038/nrg2006 Jackson, 2003, Expression profiling reveals off-target gene regulation by RNAi, Nat. Biotechnol., 21, 635, 10.1038/nbt831 Jackson, 2004, Noise amidst the silence: off-target effects of siRNAs?, Trends Genet., 20, 521, 10.1016/j.tig.2004.08.006 Kalluri, 2008, RNA interference: generic block on angiogenesis, Nature, 452, 543, 10.1038/452543a Boudreau, 2009, Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo, Mol. Ther., 17, 169, 10.1038/mt.2008.231 Grimm, 2006, Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways, Nature, 441, 537, 10.1038/nature04791 McBride, 2008, Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi, Proc. Natl. Acad. Sci. U. S. A., 105, 5868, 10.1073/pnas.0801775105 Grimm, D. et al. Argonaute proteins are key determinants of RNAi efficacy, toxicity and persistence in the adult mouse liver. J. Clin. Inv. (in press) Kim, 2008, MicroRNA-directed transcriptional gene silencing in mammalian cells, Proc. Natl. Acad. Sci. U. S. A., 105, 16230, 10.1073/pnas.0808830105 Amarzguioui, 2005, Approaches for chemically synthesized siRNA and vector-mediated RNAi, FEBS Lett., 579, 5974, 10.1016/j.febslet.2005.08.070 Rossi, 2008, Expression strategies for short hairpin RNA interference triggers, Hum. Gene Ther., 19, 313, 10.1089/hum.2008.026 Boudreau, 2008, Minimizing variables among hairpin-based RNAi vectors reveals the potency of shRNAs, RNA, 14, 1834, 10.1261/rna.1062908 Giering, 2008, Expression of shRNA from a tissue-specific pol II promoter is an effective and safe RNAi therapeutic, Mol. Ther., 16, 1630, 10.1038/mt.2008.144 Xia, 2002, siRNA-mediated gene silencing in vitro and in vivo, Nat. Biotechnol., 20, 1006, 10.1038/nbt739 Cho, 2009, Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth, Proc. Natl. Acad. Sci. U. S. A., 106, 7137, 10.1073/pnas.0812317106 Kleinman, 2008, Sequence- and target-independent angiogenesis suppression by siRNA via TLR3, Nature, 452, 591, 10.1038/nature06765 Jackson, 2010, Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application, Nat. Rev. Drug Discov., 9, 57, 10.1038/nrd3010 Holen, 2002, Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor, Nucleic Acids Res., 30, 1757, 10.1093/nar/30.8.1757 McManus, 2002, Small interfering RNA-mediated gene silencing in T lymphocytes, J. Immunol., 169, 5754, 10.4049/jimmunol.169.10.5754 Castanotto, 2007, Combinatorial delivery of small interfering RNAs reduces RNAi efficacy by selective incorporation into RISC, Nucleic Acids Res., 35, 5154, 10.1093/nar/gkm543 Koller, 2006, Competition for RISC binding predicts in vitro potency of siRNA, Nucleic Acids Res., 34, 4467, 10.1093/nar/gkl589 Vickers, 2007, Reduced levels of Ago2 expression result in increased siRNA competition in mammalian cells, Nucleic Acids Res., 35, 6598, 10.1093/nar/gkm663 Yi, 2005, Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs, RNA, 11, 220, 10.1261/rna.7233305 Yi, 2003, Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs, Genes Dev., 17, 3011, 10.1101/gad.1158803 Ehlert, 2010, Cellular toxicity following application of adeno-associated viral vector-mediated RNA interference in the nervous system, BMC Neurosci., 11, 20, 10.1186/1471-2202-11-20 Diederichs, 2008, Coexpression of Argonaute-2 enhances RNA interference toward perfect match binding sites, Proc. Natl. Acad. Sci. USA, 105, 9284, 10.1073/pnas.0800803105 Grimm, 2003, From virus evolution to vector revolution: use of naturally occurring serotypes of adeno-associated virus (AAV) as novel vectors for human gene therapy, Curr. Gene Ther., 3, 281, 10.2174/1566523034578285 Chen, 2007, Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA, Gene Ther., 14, 11, 10.1038/sj.gt.3302846 Chen, 2009, Comparative study of anti-hepatitis B virus RNA interference by double-stranded adeno-associated virus serotypes 7, 8, and 9, Mol. Ther., 17, 352, 10.1038/mt.2008.245 Su, 2009, Essential and overlapping functions for mammalian Argonautes in microRNA silencing, Genes Dev., 23, 304, 10.1101/gad.1749809 Wu, 2008, Importance of translation and nonnucleolytic ago proteins for on-target RNA interference, Curr. Biol., 18, 1327, 10.1016/j.cub.2008.07.072 Keck, 2009, Rational design leads to more potent RNA interference against hepatitis B virus: factors effecting silencing efficiency, Mol. Ther., 17, 538, 10.1038/mt.2008.273 Liu, 2009, Combinatorial RNAi against HIV-1 using extended short hairpin RNAs, Mol. Ther., 17, 1712, 10.1038/mt.2009.176 Saayman, S. et al. Deriving four functional anti-HIV siRNAs from a single Pol III-generated transcript comprising two adjacent long hairpin RNA precursors. Nucleic Acids Res. (in press) Doege, 2008, Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia, J. Biol. Chem., 283, 22186, 10.1074/jbc.M803510200 Grimm, 2008, In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses, J. Virol., 82, 5887, 10.1128/JVI.00254-08 Vandenberghe, 2009, Tailoring the AAV vector capsid for gene therapy, Gene Ther., 16, 311, 10.1038/gt.2008.170 Beer, 2010, Low-level shRNA cytotoxicity can contribute to MYC-induced hepatocellular carcinoma in adult mice, Mol. Ther., 18, 161, 10.1038/mt.2009.222