Small silencing RNAs: State-of-the-art

Advanced Drug Delivery Reviews

Volumn 61, Issue 9, 2009, Pages 672-703

  Grimm, Dirk ^a  

^a UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

AAV vectors; Gene therapy; Micro RNA; Short hairpin RNA; Small interfering RNA; Transcriptional regulation

Indexed keywords

AAV VECTORS; GENE THERAPY; MICRO-RNA; SHORT HAIRPIN RNA; SMALL INTERFERING RNA; TRANSCRIPTIONAL REGULATION;

DISEASE CONTROL; GENETIC ENGINEERING; RNA; TRANSCRIPTION; VECTORS;

NUCLEIC ACIDS;

ADENOVIRUS VECTOR; MICRORNA; NUCLEOSIDE ANALOG; NUCLEOTIDE DERIVATIVE; ONCOLYTIC VIRUS; PARVOVIRUS VECTOR; PEGINTERFERON ALPHA; SHORT HAIRPIN RNA; SMALL INTERFERING RNA;

ANTINEOPLASTIC ACTIVITY; DEGENERATIVE DISEASE; DRUG ACTIVITY; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG MECHANISM; DRUG SAFETY; GENE ACTIVATION; GENE EXPRESSION; GENE SILENCING; GENE THERAPY; GENETIC TRANSCRIPTION; HEPATITIS B; HUMAN; HUNTINGTON CHOREA; NONHUMAN; PRIORITY JOURNAL; REVIEW; RNA INTERFERENCE;

ADJUVANTS, IMMUNOLOGIC; ANIMALS; DEPENDOVIRUS; GENE SILENCING; GENE THERAPY; GENETIC VECTORS; HUMANS; MICRORNAS; RNA INTERFERENCE; RNA, SMALL INTERFERING; TRANSCRIPTIONAL ACTIVATION;

EID: 65749110883     PISSN: 0169409X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.addr.2009.05.002     Document Type: Review

References (174)

1. Fire A., Xu S., Montgomery M.K., Kostas S.A., Driver S.E., and Mello C.C. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391 (1998) 806-811
2. Elbashir S.M., Harborth J., Lendeckel W., Yalcin A., Weber K., and Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411 (2001) 494-498
3. Meister G., and Tuschl T. Mechanisms of gene silencing by double-stranded RNA. Nature 431 (2004) 343-349
4. Hannon G.J., and Rossi J.J. Unlocking the potential of the human genome with RNA interference. Nature 431 (2004) 371-378
5. Dykxhoorn D.M., and Lieberman J. The silent revolution: RNA interference as basic biology, research tool, and therapeutic. Annu. Rev. Med. 56 (2005) 401-423
6. Tomari Y., and Zamore P.D. Perspective: machines for RNAi. Genes Dev. 19 (2005) 517-529
7. Kim D.H., and Rossi J.J. Strategies for silencing human disease using RNA interference. Nat. Rev., Genet. 8 (2007) 173-184
8. Lagos-Quintana M., Rauhut R., Lendeckel W., and Tuschl T. Identification of novel genes coding for small expressed RNAs. Science 294 (2001) 853-858
9. Lagos-Quintana M., Rauhut R., Yalcin A., Meyer J., Lendeckel W., and Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr. Biol. 12 (2002) 735-739
10. Carthew R.W., and Sontheimer E.J. Origins and mechanisms of miRNAs and siRNAs. Cell 136 (2009) 642-655
11. Kim V.N., Han J., and Siomi M.C. Biogenesis of small RNAs in animals. Nat. Rev., Mol. Cell Biol. 10 (2009) 126-139
12. Brodersen P., and Voinnet O. Revisiting the principles of microRNA target recognition and mode of action. Nat. Rev., Mol. Cell Biol. 10 (2009) 141-148
13. Bartel D.P. MicroRNAs: target recognition and regulatory functions. Cell 136 (2009) 215-233
14. Filipowicz W., Bhattacharyya S.N., and Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?. Nat. Rev., Genet. 9 (2008) 102-114
15. He L., and Hannon G.J. MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev., Genet. 5 (2004) 522-531
16. Lee R.C., Feinbaum R.L., and Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75 (1993) 843-854
17. Pei Y., and Tuschl T. On the art of identifying effective and specific siRNAs. Nat. Methods 3 (2006) 670-676
18. Elbashir S.M., Lendeckel W., and Tuschl T. RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev. 15 (2001) 188-200
19. Hutvagner G., and Simard M.J. Argonaute proteins: key players in RNA silencing. Nat. Rev., Mol. Cell Biol. 9 (2008) 22-32
20. Tolia N.H., and Joshua-Tor L. Slicer and the argonautes. Nat. Chem. Biol. 3 (2007) 36-43
21. Song J.J., and Joshua-Tor L. Argonaute and RNA - getting into the groove. Curr. Opin. Struct. Biol. 16 (2006) 5-11
22. Hock J., and Meister G. The Argonaute protein family. Genome Biol. 9 (2008) 210
23. Paul C.P., Good P.D., Winer I., and Engelke D.R. Effective expression of small interfering RNA in human cells. Nat. Biotechnol. 20 (2002) 505-508
24. Yu J.Y., DeRuiter S.L., and Turner D.L. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 6047-6052
25. Rossi J.J. Expression strategies for short hairpin RNA interference triggers. Hum. Gene Ther. 19 (2008) 313-317
26. Grimm D., and Kay M.A. RNAi and gene therapy: a mutual attraction. Hematology (Am. Soc. Hematol. Educ. Program) 2007 (2007) 473-481
27. Brummelkamp T.R., Bernards R., and Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296 (2002) 550-553
28. Paddison P.J., Caudy A.A., Bernstein E., Hannon G.J., and Conklin D.S. Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev. 16 (2002) 948-958
29. Whitehead K.A., Langer R., and Anderson D.G. Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug Discov. 8 (2009) 129-138
30. Martin S.E., and Caplen N.J. Applications of RNA interference in mammalian systems. Annu. Rev. Genomics Hum. Genet. 8 (2007) 81-108
31. Castanotto D., and Rossi J.J. The promises and pitfalls of RNA-interference-based therapeutics. Nature 457 (2009) 426-433
32. Grimm D., and Kay M.A. Therapeutic application of RNAi: is mRNA targeting finally ready for prime time?. J. Clin. Invest. 117 (2007) 3633-3641
33. Grimm D., and Kay M.A. Combinatorial RNAi: a winning strategy for the race against evolving targets?. Mol. Ther. 15 (2007) 878-888
34. Behlke M.A. Chemical modification of siRNAs for in vivo use. Oligonucleotides 18 (2008) 305-319
35. Burchard J., Jackson A.L., Malkov V., Needham R.H., Tan Y., Bartz S.R., Dai H., Sachs A.B., and Linsley P.S. MicroRNA-like off-target transcript regulation by siRNAs is species specific. RNA 15 (2009) 308-315
36. Jackson A.L., Burchard J., Schelter J., Chau B.N., Cleary M., Lim L., and Linsley P.S. Widespread siRNA "off-target" transcript silencing mediated by seed region sequence complementarity. RNA 12 (2006) 1179-1187
37. Jackson A.L., and Linsley P.S. Noise amidst the silence: off-target effects of siRNAs?. Trends Genet. 20 (2004) 521-524
38. Jackson A.L., Bartz S.R., Schelter J., Kobayashi S.V., Burchard J., Mao M., Li B., Cavet G., and Linsley P.S. Expression profiling reveals off-target gene regulation by RNAi. Nat. Biotechnol. 21 (2003) 635-637
39. Corey D.R. Chemical modification: the key to clinical application of RNA interference?. J. Clin. Invest. 117 (2007) 3615-3622
40. Schlee M., Hornung V., and Hartmann G. siRNA and isRNA: two edges of one sword. Mol. Ther. 14 (2006) 463-470
41. Judge A., and MacLachlan I. Overcoming the innate immune response to small interfering RNA. Hum. Gene Ther. 19 (2008) 111-124
42. Grimm D., Pandey K., and Kay M.A. Adeno-associated virus vectors for short hairpin RNA expression. Methods Enzymol. 392 (2005) 381-405
43. Grimm D., and Kay M.A. 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 (2003) 281-304
44. Grimm D., Streetz K.L., Jopling C.L., Storm T.A., Pandey K., Davis C.R., Marion P., Salazar F., and Kay M.A. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441 (2006) 537-541
45. Castanotto D., Sakurai K., Lingeman R., Li H., Shively L., Aagaard L., Soifer H., Gatignol A., Riggs A., and Rossi J.J. Combinatorial delivery of small interfering RNAs reduces RNAi efficacy by selective incorporation into RISC. Nucleic Acids Res. 35 (2007) 5154-5164
46. Rana T.M. Illuminating the silence: understanding the structure and function of small RNAs. Nat. Rev., Mol. Cell Biol. 8 (2007) 23-36
47. Ghildiyal M., and Zamore P.D. Small silencing RNAs: an expanding universe. Nat. Rev., Genet. 10 (2009) 94-108
48. Lagos-Quintana M., Rauhut R., Meyer J., Borkhardt A., and Tuschl T. New microRNAs from mouse and human. RNA 9 (2003) 175-179
49. Garofalo M., Condorelli G., and Croce C.M. MicroRNAs in diseases and drug response. Curr. Opin. Pharmacol. 8 (2008) 661-667
50. Mattes J., Collison A., and Foster P.S. Emerging role of microRNAs in disease pathogenesis and strategies for therapeutic modulation. Curr. Opin. Mol. Ther. 10 (2008) 150-157
51. Medina P.P., and Slack F.J. MicroRNAs and cancer: an overview. Cell Cycle 7 (2008) 2485-2492
52. Jackson A.L., Burchard J., Leake D., Reynolds A., Schelter J., Guo J., Johnson J.M., Lim L., Karpilow J., Nichols K., Marshall W., Khvorova A., and Linsley P.S. Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing. RNA 12 (2006) 1197-1205
53. Birmingham A., Anderson E.M., Reynolds A., Ilsley-Tyree D., Leake D., Fedorov Y., Baskerville S., Maksimova E., Robinson K., Karpilow J., Marshall W.S., and Khvorova A. 3′ UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat. Methods 3 (2006) 199-204
54. Anderson E.M., Birmingham A., Baskerville S., Reynolds A., Maksimova E., Leake D., Fedorov Y., Karpilow J., and Khvorova A. Experimental validation of the importance of seed complement frequency to siRNA specificity. RNA 14 (2008) 853-861
55. Fedorov Y., Anderson E.M., Birmingham A., Reynolds A., Karpilow J., Robinson K., Leake D., Marshall W.S., and Khvorova A. Off-target effects by siRNA can induce toxic phenotype. RNA 12 (2006) 1188-1196
56. Ui-Tei K., Naito Y., Nishi K., Juni A., and Saigo K. Thermodynamic stability and Watson-Crick base pairing in the seed duplex are major determinants of the efficiency of the siRNA-based off-target effect. Nucleic Acids Res. 36 (2008) 7100-7109
57. Birmingham A., Anderson E., Sullivan K., Reynolds A., Boese Q., Leake D., Karpilow J., and Khvorova A. A protocol for designing siRNAs with high functionality and specificity. Nat. Protoc. 2 (2007) 2068-2078
58. Reynolds A., Leake D., Boese Q., Scaringe S., Marshall W.S., and Khvorova A. Rational siRNA design for RNA interference. Nat. Biotechnol. 22 (2004) 326-330
59. J.B. Bramsen, M.B. Laursen, A.F. Nielsen, T.B. Hansen, C. Bus, N. Langkjaer, B.R. Babu, T. Hojland, M. Abramov, A. Van Aerschot, D. Odadzic, R. Smicius, J. Haas, C. Andree, J. Barman, M. Wenska, P. Srivastava, C. Zhou, D. Honcharenko, S. Hess, E. Muller, G.V. Bobkov, S.N. Mikhailov, E. Fava, T.F. Meyer, J. Chattopadhyaya, M. Zerial, J.W. Engels, P. Herdewijn, J. Wengel, J. Kjems, A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity, Nucleic Acids Res. (in press) (2009, Electronic publication ahead of print), doi:10.1093/nar/gkp106.
60. Patzel V., Rutz S., Dietrich I., Koberle C., Scheffold A., and Kaufmann S.H. Design of siRNAs producing unstructured guide-RNAs results in improved RNA interference efficiency. Nat. Biotechnol. 23 (2005) 1440-1444
61. Kim D.H., Behlke M.A., Rose S.D., Chang M.S., Choi S., and Rossi J.J. Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat. Biotechnol. 23 (2005) 222-226
62. Siolas D., Lerner C., Burchard J., Ge W., Linsley P.S., Paddison P.J., Hannon G.J., and Cleary M.A. Synthetic shRNAs as potent RNAi triggers. Nat. Biotechnol. 23 (2005) 227-231
63. Williams B.R. Dicing with siRNA. Nat. Biotechnol. 23 (2005) 181-182
64. Rose S.D., Kim D.H., Amarzguioui M., Heidel J.D., Collingwood M.A., Davis M.E., Rossi J.J., and Behlke M.A. Functional polarity is introduced by Dicer processing of short substrate RNAs. Nucleic Acids Res. 33 (2005) 4140-4156
65. Chen P.Y., Weinmann L., Gaidatzis D., Pei Y., Zavolan M., Tuschl T., and Meister G. Strand-specific 5′-O-methylation of siRNA duplexes controls guide strand selection and targeting specificity. RNA 14 (2008) 263-274
66. Vermeulen A., Behlen L., Reynolds A., Wolfson A., Marshall W.S., Karpilow J., and Khvorova A. The contributions of dsRNA structure to Dicer specificity and efficiency. RNA 11 (2005) 674-682
67. Chu C.Y., and Rana T.M. Potent RNAi by short RNA triggers. RNA 14 (2008) 1714-1719
68. Sano M., Sierant M., Miyagishi M., Nakanishi M., Takagi Y., and Sutou S. Effect of asymmetric terminal structures of short RNA duplexes on the RNA interference activity and strand selection. Nucleic Acids Res. 36 (2008) 5812-5821
69. Sun X., Rogoff H.A., and Li C.J. Asymmetric RNA duplexes mediate RNA interference in mammalian cells. Nat. Biotechnol. 26 (2008) 1379-1382
70. Hossbach M., Gruber J., Osborn M., Weber K., and Tuschl T. Gene silencing with siRNA duplexes composed of target-mRNA-complementary and partially palindromic or partially complementary single-stranded siRNAs. RNA Biol. 3 (2006) 82-89
71. Bramsen J.B., Laursen M.B., Damgaard C.K., Lena S.W., Babu B.R., Wengel J., and Kjems J. Improved silencing properties using small internally segmented interfering RNAs. Nucleic Acids Res. 35 (2007) 5886-5897
72. Hornung V., Barchet W., Schlee M., and Hartmann G. RNA recognition via TLR7 and TLR8. Handb. Exp. Pharmacol. (2008) 71-86
73. Schlee M., Barchet W., Hornung V., and Hartmann G. Beyond double-stranded RNA-type I IFN induction by 3pRNA and other viral nucleic acids. Curr. Top. Microbiol. Immunol. 316 (2007) 207-230
74. Reynolds A., Anderson E.M., Vermeulen A., Fedorov Y., Robinson K., Leake D., Karpilow J., Marshall W.S., and Khvorova A. Induction of the interferon response by siRNA is cell type- and duplex length-dependent. RNA 12 (2006) 988-993
75. Petrocca F., and Lieberman J. RIG-ing an antitumor response. Nat. Med. 14 (2008) 1152-1153
76. Poeck H., Besch R., Maihoefer C., Renn M., Tormo D., Morskaya S.S., Kirschnek S., Gaffal E., Landsberg J., Hellmuth J., Schmidt A., Anz D., Bscheider M., Schwerd T., Berking C., Bourquin C., Kalinke U., Kremmer E., Kato H., Akira S., Meyers R., Hacker G., Neuenhahn M., Busch D., Ruland J., Rothenfusser S., Prinz M., Hornung V., Endres S., Tuting T., and Hartmann G. 5′-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat. Med. 14 (2008) 1256-1263
77. Robbins M.A., and Rossi J.J. Sensing the danger in RNA. Nat. Med. 11 (2005) 250-251
78. Robbins M.A., Li M., Leung I., Li H., Boyer D.V., Song Y., Behlke M.A., and Rossi J.J. Stable expression of shRNAs in human CD34+ progenitor cells can avoid induction of interferon responses to siRNAs in vitro. Nat. Biotechnol. 24 (2006) 566-571
79. Hornung V., Guenthner-Biller M., Bourquin C., Ablasser A., Schlee M., Uematsu S., Noronha A., Manoharan M., Akira S., de Fougerolles A., Endres S., and Hartmann G. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat. Med. 11 (2005) 263-270
80. Marques J.T., Devosse T., Wang D., Zamanian-Daryoush M., Serbinowski P., Hartmann R., Fujita T., Behlke M.A., and Williams B.R. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat. Biotechnol. 24 (2006) 559-565
81. Kleinman M.E., Yamada K., Takeda A., Chandrasekaran V., Nozaki M., Baffi J.Z., Albuquerque R.J., Yamasaki S., Itaya M., Pan Y., Appukuttan B., Gibbs D., Yang Z., Kariko K., Ambati B.K., Wilgus T.A., DiPietro L.A., Sakurai E., Zhang K., Smith J.R., Taylor E.W., and Ambati J. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452 (2008) 591-597
82. Robbins M., Judge A., Ambegia E., Choi C., Yaworski E., Palmer L., McClintock K., and Maclachlan I. Misinterpreting the therapeutic effects of siRNA caused by immune stimulation. Hum. Gene Ther. 19 (2008) 991-999
83. Hornung V., Ellegast J., Kim S., Brzozka K., Jung A., Kato H., Poeck H., Akira S., Conzelmann K.K., Schlee M., Endres S., and Hartmann G. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314 (2006) 994-997
84. Peng Y., Lu J.X., and Shen X.F. shRNA driven by Pol II/T7 dual-promoter system effectively induce cell-specific RNA interference in mammalian cells. Biochem. Biophys. Res. Commun. 360 (2007) 496-500
85. Giering J.C., Grimm D., Storm T.A., and Kay M.A. Expression of shRNA from a tissue-specific pol II promoter is an effective and safe RNAi therapeutic. Mol. Ther. 16 (2008) 1630-1636
86. Matzke M.A., and Birchler J.A. RNAi-mediated pathways in the nucleus. Nat. Rev., Genet. 6 (2005) 24-35
87. Morris K.V., Chan S.W., Jacobsen S.E., and Looney D.J. Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305 (2004) 1289-1292
88. Ting A.H., Schuebel K.E., Herman J.G., and Baylin S.B. Short double-stranded RNA induces transcriptional gene silencing in human cancer cells in the absence of DNA methylation. Nat. Genet. 37 (2005) 906-910
89. Castanotto D., Tommasi S., Li M., Li H., Yanow S., Pfeifer G.P., and Rossi J.J. Short hairpin RNA-directed cytosine (CpG) methylation of the RASSF1A gene promoter in HeLa cells. Mol. Ther. 12 (2005) 179-183
90. Janowski B.A., Huffman K.E., Schwartz J.C., Ram R., Hardy D., Shames D.S., Minna J.D., and Corey D.R. Inhibiting gene expression at transcription start sites in chromosomal DNA with antigene RNAs. Nat. Chem. Biol. 1 (2005) 216-222
91. Weinberg M.S., Villeneuve L.M., Ehsani A., Amarzguioui M., Aagaard L., Chen Z.X., Riggs A.D., Rossi J.J., and Morris K.V. The antisense strand of small interfering RNAs directs histone methylation and transcriptional gene silencing in human cells. RNA 12 (2006) 256-262
92. Kim D.H., Villeneuve L.M., Morris K.V., and Rossi J.J. Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. Nat. Struct. Mol. Biol. 13 (2006) 793-797
93. Janowski B.A., Huffman K.E., Schwartz J.C., Ram R., Nordsell R., Shames D.S., Minna J.D., and Corey D.R. Involvement of AGO1 and AGO2 in mammalian transcriptional silencing. Nat. Struct. Mol. Biol. 13 (2006) 787-792
94. Han J., Kim D., and Morris K.V. Promoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 12422-12427
95. Suzuki K., Juelich T., Lim H., Ishida T., Watanebe T., Cooper D.A., Rao S., and Kelleher A.D. Closed chromatin architecture is induced by an RNA duplex targeting the HIV-1 promoter region. J. Biol. Chem. 283 (2008) 23353-23363
96. Lim H.G., Suzuki K., Cooper D.A., and Kelleher A.D. Promoter-targeted siRNAs induce gene silencing of simian immunodeficiency virus (SIV) infection in vitro. Mol. Ther. 16 (2008) 565-570
97. Kim D.H., Saetrom P., Snove Jr. O., and Rossi J.J. MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 16230-16235
98. Huang J., Wang F., Argyris E., Chen K., Liang Z., Tian H., Huang W., Squires K., Verlinghieri G., and Zhang H. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat. Med. 13 (2007) 1241-1247
99. Suzuki K., Shijuuku T., Fukamachi T., Zaunders J., Guillemin G., Cooper D., and Kelleher A. Prolonged transcriptional silencing and CpG methylation induced by siRNAs targeted to the HIV-1 promoter region. J. RNAi Gene Sil. 1 (2005) 66-78
100. Li L.C., Okino S.T., Zhao H., Pookot D., Place R.F., Urakami S., Enokida H., and Dahiya R. Small dsRNAs induce transcriptional activation in human cells. Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 17337-17342
101. Janowski B.A., Younger S.T., Hardy D.B., Ram R., Huffman K.E., and Corey D.R. Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat. Chem. Biol. 3 (2007) 166-173
102. Schwartz J.C., Younger S.T., Nguyen N.B., Hardy D.B., Monia B.P., Corey D.R., and Janowski B.A. Antisense transcripts are targets for activating small RNAs. Nat. Struct. Mol. Biol. 15 (2008) 842-848
103. Place R.F., Li L.C., Pookot D., Noonan E.J., and Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 1608-1613
104. Weinberg M.S., Barichievy S., Schaffer L., Han J., and Morris K.V. An RNA targeted to the HIV-1 LTR promoter modulates indiscriminate off-target gene activation. Nucleic Acids Res. 35 (2007) 7303-7312
105. Morris K.V., Santoso S., Turner A.M., Pastori C., and Hawkins P.G. Bidirectional transcription directs both transcriptional gene activation and suppression in human cells. PLoS Genet. 4 (2008) e1000258
106. Chen Z., Place R.F., Jia Z.J., Pookot D., Dahiya R., and Li L.C. Antitumor effect of dsRNA-induced p21(WAF1/CIP1) gene activation in human bladder cancer cells. Mol. Cancer Ther. 7 (2008) 698-703
107. Yang K., Zheng X.Y., Qin J., Wang Y.B., Bai Y., Mao Q.Q., Wan Q., Wu Z.M., and Xie L.P. Up-regulation of p21WAF1/Cip1 by saRNA induces G1-phase arrest and apoptosis in T24 human bladder cancer cells. Cancer Lett. 265 (2008) 206-214
108. Mao Q., Li Y., Zheng X., Yang K., Shen H., Qin J., Bai Y., Kong D., Jia X., and Xie L. Up-regulation of E-cadherin by small activating RNA inhibits cell invasion and migration in 5637 human bladder cancer cells. Biochem. Biophys. Res. Commun. 375 (2008) 566-570
109. Grimm D., and Kay M.A. Therapeutic short hairpin RNA expression in the liver: viral targets and vectors. Gene Ther. 13 (2006) 563-575
110. Grimm D., Lee J.S., Wang L., Desai T., Akache B., Storm T.A., and Kay M.A. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J. Virol. 82 (2008) 5887-5911
111. Li L., Yang L., Scudiero D.A., Miller S.A., Yu Z.X., Stukenberg P.T., Shoemaker R.H., and Kotin R.M. Development of recombinant adeno-associated virus vectors carrying small interfering RNA (shHec1)-mediated depletion of kinetochore Hec1 protein in tumor cells. Gene Ther. 14 (2007) 814-827
112. Park K., Kim W.J., Cho Y.H., Lee Y.I., Lee H., Jeong S., Cho E.S., Chang S.I., Moon S.K., Kang B.S., Kim Y.J., and Cho S.H. Cancer gene therapy using adeno-associated virus vectors. Front. Biosci. 13 (2008) 2653-2659
113. Li X., Liu X., Li C.Y., Ding Y., Chau D., Li G., Kung H.F., Lin M.C., and Peng Y. Recombinant adeno-associated virus mediated RNA interference inhibits metastasis of nasopharyngeal cancer cells in vivo and in vitro by suppression of Epstein-Barr virus encoded LMP-1. Int. J. Oncol. 29 (2006) 595-603
114. Doege H., Grimm D., Falcon A., Tsang B., Storm T.A., Xu H., Ortegon A.M., Kazantzis M., Kay M.A., and Stahl A. 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 (2008) 22186-22192
115. Garza J.C., Kim C.S., Liu J., Zhang W., and Lu X.Y. Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity. J. Endocrinol. 197 (2008) 471-482
116. Musatov S., Chen W., Pfaff D.W., Mobbs C.V., Yang X.J., Clegg D.J., Kaplitt M.G., and Ogawa S. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 2501-2506
117. Musatov S., Chen W., Pfaff D.W., Kaplitt M.G., and Ogawa S. RNAi-mediated silencing of estrogen receptor {alpha} in the ventromedial nucleus of hypothalamus abolishes female sexual behaviors. Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 10456-10460
118. Sun Z., Bello-Roufai M., and Wang X. RNAi inhibition of mineralocorticoid receptors prevents the development of cold-induced hypertension. Am. J. Physiol., Heart Circ. Physiol. 294 (2008) H1880-1887
119. Andino L.M., Takeda M., Kasahara H., Jakymiw A., Byrne B.J., and Lewin A.S. AAV-mediated knockdown of phospholamban leads to improved contractility and calcium handling in cardiomyocytes. J. Gene Med. 10 (2008) 132-142
120. Fechner H., Sipo I., Westermann D., Pinkert S., Wang X., Suckau L., Kurreck J., Zeichhardt H., Muller O., Vetter R., Erdmann V., Tschope C., and Poller W. Cardiac-targeted RNA interference mediated by an AAV9 vector improves cardiac function in coxsackievirus B3 cardiomyopathy. J. Mol. Med. 86 (2008) 987-997
121. O'Reilly M., Palfi A., Chadderton N., Millington-Ward S., Ader M., Cronin T., Tuohy T., Auricchio A., Hildinger M., Tivnan A., McNally N., Humphries M.M., Kiang A.S., Humphries P., Kenna P.F., and Farrar G.J. RNA interference-mediated suppression and replacement of human rhodopsin in vivo. Am. J. Hum. Genet. 81 (2007) 127-135
122. Paskowitz D.M., Greenberg K.P., Yasumura D., Grimm D., Yang H., Duncan J.L., Kay M.A., Lavail M.M., Flannery J.G., and Vollrath D. Rapid and stable knockdown of an endogenous gene in retinal pigment epithelium. Hum. Gene Ther. 18 (2007) 871-880
123. Xia H., Mao Q., Eliason S.L., Harper S.Q., Martins I.H., Orr H.T., Paulson H.L., Yang L., Kotin R.M., and Davidson B.L. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat. Med. 10 (2004) 816-820
124. Harper S.Q., Staber P.D., He X., Eliason S.L., Martins I.H., Mao Q., Yang L., Kotin R.M., Paulson H.L., and Davidson B.L. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 5820-5825
125. Rodriguez-Lebron E., Denovan-Wright E.M., Nash K., Lewin A.S., and Mandel R.J. Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington's disease transgenic mice. Mol. Ther. 12 (2005) 618-633
126. Denovan-Wright E.M., Rodriguez-Lebron E., Lewin A.S., and Mandel R.J. Unexpected off-targeting effects of anti-huntingtin ribozymes and siRNA in vivo. Neurobiol. Dis. 29 (2008) 446-455
127. Franich N.R., Fitzsimons H.L., Fong D.M., Klugmann M., During M.J., and Young D. AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease. Mol. Ther. 16 (2008) 947-956
128. DiFiglia M., Sena-Esteves M., Chase K., Sapp E., Pfister E., Sass M., Yoder J., Reeves P., Pandey R.K., Rajeev K.G., Manoharan M., Sah D.W., Zamore P.D., and Aronin N. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 17204-17209
129. Towne C., Raoul C., Schneider B.L., and Aebischer P. Systemic AAV6 delivery mediating RNA interference against SOD1: neuromuscular transduction does not alter disease progression in fALS mice. Mol. Ther. 16 (2008) 1018-1025
130. Ghahramani Seno M.M., Graham I.R., Athanasopoulos T., Trollet C., Pohlschmidt M., Crompton M.R., and Dickson G. RNAi-mediated knockdown of dystrophin expression in adult mice does not lead to overt muscular dystrophy pathology. Hum. Mol. Genet. 17 (2008) 2622-2632
131. Grimm D., Pandey K., Nakai H., Storm T.A., and Kay M.A. Liver transduction with recombinant adeno-associated virus is primarily restricted by capsid serotype not vector genotype. J. Virol. 80 (2006) 426-439
132. Chen C.C., Ko T.M., Ma H.I., Wu H.L., Xiao X., Li J., Chang C.M., Wu P.Y., Chen C.H., Han J.M., Yu C.P., Jeng K.S., Hu C.P., and Tao M.H. Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA. Gene Ther. 14 (2007) 11-19
133. Chen C.C., Sun C.P., Ma H.I., Fang C.C., Wu P.Y., Xiao X., and Tao M.H. Comparative study of anti-hepatitis B virus RNA interference by double-stranded adeno-associated virus serotypes 7, 8, and 9. Mol. Ther. 17 (2009) 352-359
134. Calcedo R., Vandenberghe L.H., Gao G., Lin J., and Wilson J.M. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 199 (2009) 381-390
135. Boden D., Pusch O., Lee F., Tucker L., and Ramratnam B. Efficient gene transfer of HIV-1-specific short hairpin RNA into human lymphocytic cells using recombinant adeno-associated virus vectors. Mol. Ther. 9 (2004) 396-402
136. Boudreau R.L., Martins I., and Davidson B.L. Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Mol. Ther. 17 (2009) 169-175
137. McBride J.L., Boudreau R.L., Harper S.Q., Staber P.D., Monteys A.M., Martins I., Gilmore B.L., Burstein H., Peluso R.W., Polisky B., Carter B.J., and Davidson B.L. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 5868-5873
138. Bridge A.J., Pebernard S., Ducraux A., Nicoulaz A.L., and Iggo R. Induction of an interferon response by RNAi vectors in mammalian cells. Nat. Genet. 34 (2003) 263-264
139. Fish R.J., and Kruithof E.K. Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors. BMC Mol. Biol. 5 (2004) 9
140. Yi R., Qin Y., Macara I.G., and Cullen B.R. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 17 (2003) 3011-3016
141. Diederichs S., Jung S., Rothenberg S.M., Smolen G.A., Mlody B.G., and Haber D.A. Coexpression of Argonaute-2 enhances RNA interference toward perfect match binding sites. Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 9284-9289
142. Boudreau R.L., Monteys A.M., and Davidson B.L. Minimizing variables among hairpin-based RNAi vectors reveals the potency of shRNAs. RNA 14 (2008) 1834-1844
143. Brown B.D., Venneri M.A., Zingale A., Sergi Sergi L., and Naldini L. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nat. Med. 12 (2006) 585-591
144. Brown B.D., Cantore A., Annoni A., Sergi L.S., Lombardo A., Della Valle P., D'Angelo A., and Naldini L. A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice. Blood 110 (2007) 4144-4152
145. Brown B.D., Gentner B., Cantore A., Colleoni S., Amendola M., Zingale A., Baccarini A., Lazzari G., Galli C., and Naldini L. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nat. Biotechnol. 25 (2007) 1457-1467
146. Kelly E.J., Hadac E.M., Greiner S., and Russell S.J. Engineering microRNA responsiveness to decrease virus pathogenicity. Nat. Med. 14 (2008) 1278-1283
147. Kelly E.J., and Russell S.J. MicroRNAs and the regulation of vector tropism. Mol. Ther. 17 (2009) 409-416
148. Ylosmaki E., Hakkarainen T., Hemminki A., Visakorpi T., Andino R., and Saksela K. Generation of a conditionally replicating adenovirus based on targeted destruction of E1A mRNA by a cell type-specific MicroRNA. J. Virol. 82 (2008) 11009-11015
149. Edge R.E., Falls T.J., Brown C.W., Lichty B.D., Atkins H., and Bell J.C. A let-7 MicroRNA-sensitive vesicular stomatitis virus demonstrates tumor-specific replication. Mol. Ther. 16 (2008) 1437-1443
150. Bell J.C., and Kirn D. MicroRNAs fine-tune oncolytic viruses. Nat. Biotechnol. 26 (2008) 1346-1348
151. Jopling C.L., Yi M., Lancaster A.M., Lemon S.M., and Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309 (2005) 1577-1581
152. Krutzfeldt J., Rajewsky N., Braich R., Rajeev K.G., Tuschl T., Manoharan M., and Stoffel M. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438 (2005) 685-689
153. Care A., Catalucci D., Felicetti F., Bonci D., Addario A., Gallo P., Bang M.L., Segnalini P., Gu Y., Dalton N.D., Elia L., Latronico M.V., Hoydal M., Autore C., Russo M.A., Dorn II G.W., Ellingsen O., Ruiz-Lozano P., Peterson K.L., Croce C.M., Peschle C., and Condorelli G. MicroRNA-133 controls cardiac hypertrophy. Nat. Med. 13 (2007) 613-618
154. Scherr M., Venturini L., Battmer K., Schaller-Schoenitz M., Schaefer D., Dallmann I., Ganser A., and Eder M. Lentivirus-mediated antagomir expression for specific inhibition of miRNA function. Nucleic Acids Res. 35 (2007) e149
155. Ebert M.S., Neilson J.R., and Sharp P.A. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat. Methods 4 (2007) 721-726
156. Gentner B., Schira G., Giustacchini A., Amendola M., Brown B.D., Ponzoni M., and Naldini L. Stable knockdown of microRNA in vivo by lentiviral vectors. Nat. Methods 6 (2009) 63-66
157. Haraguchi T., Ozaki Y., and Iba H. Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res. 37 (2009) e43
158. Calin G.A., and Croce C.M. MicroRNA signatures in human cancers. Nat. Rev. Cancer 6 (2006) 857-866
159. Valadi H., Ekstrom K., Bossios A., Sjostrand M., Lee J.J., and Lotvall J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9 (2007) 654-659
160. Chim S.S., Shing T.K., Hung E.C., Leung T.Y., Lau T.K., Chiu R.W., and Lo Y.M. Detection and characterization of placental microRNAs in maternal plasma. Clin. Chem. 54 (2008) 482-490
161. Gilad S., Meiri E., Yogev Y., Benjamin S., Lebanony D., Yerushalmi N., Benjamin H., Kushnir M., Cholakh H., Melamed N., Bentwich Z., Hod M., Goren Y., and Chajut A. Serum microRNAs are promising novel biomarkers. PLoS ONE 3 (2008) e3148
162. Lawrie C.H., Gal S., Dunlop H.M., Pushkaran B., Liggins A.P., Pulford K., Banham A.H., Pezzella F., Boultwood J., Wainscoat J.S., Hatton C.S., and Harris A.L. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br. J. Haematol. 141 (2008) 672-675
163. Mitchell P.S., Parkin R.K., Kroh E.M., Fritz B.R., Wyman S.K., Pogosova-Agadjanyan E.L., Peterson A., Noteboom J., O'Briant K.C., Allen A., Lin D.W., Urban N., Drescher C.W., Knudsen B.S., Stirewalt D.L., Gentleman R., Vessella R.L., Nelson P.S., Martin D.B., and Tewari M. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 10513-10518
164. Chen X., Ba Y., Ma L., Cai X., Yin Y., Wang K., Guo J., Zhang Y., Chen J., Guo X., Li Q., Li X., Wang W., Zhang Y., Wang J., Jiang X., Xiang Y., Xu C., Zheng P., Zhang J., Li R., Zhang H., Shang X., Gong T., Ning G., Wang J., Zen K., Zhang J., and Zhang C.Y. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 18 (2008) 997-1006
165. Wang K., Zhang S., Marzolf B., Troisch P., Brightman A., Hu Z., Hood L.E., and Galas D.J. Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 4402-4407
166. Skog J., Wurdinger T., van Rijn S., Meijer D.H., Gainche L., Sena-Esteves M., Curry Jr. W.T., Carter B.S., Krichevsky A.M., and Breakefield X.O. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10 (2008) 1470-1476
167. Hunter M.P., Ismail N., Zhang X., Aguda B.D., Lee E.J., Yu L., Xiao T., Schafer J., Lee M.L., Schmittgen T.D., Nana-Sinkam S.P., Jarjoura D., and Marsh C.B. Detection of microRNA expression in human peripheral blood microvesicles. PLoS ONE 3 (2008) e3694
168. Stadler B.M., and Ruohola-Baker H. Small RNAs: keeping stem cells in line. Cell 132 (2008) 563-566
169. de Vries W., and Berkhout B. RNAi suppressors encoded by pathogenic human viruses. Int. J. Biochem. Cell Biol. 40 (2008) 2007-2012
170. Cullen B.R. Viruses and microRNAs. Nat. Genet. 38 (2006) S25-S30 (Suppl)
171. Sarnow P., Jopling C.L., Norman K.L., Schutz S., and Wehner K.A. MicroRNAs: expression, avoidance and subversion by vertebrate viruses. Nat. Rev. Microbiol. 4 (2006) 651-659
172. Boutros M., and Ahringer J. The art and design of genetic screens: RNA interference. Nat. Rev., Genet. 9 (2008) 554-566
173. Okamura K., and Lai E.C. Endogenous small interfering RNAs in animals. Nat. Rev., Mol. Cell Biol. 9 (2008) 673-678
174. Golden D.E., Gerbasi V.R., and Sontheimer E.J. An inside job for siRNAs. Mol. Cell 31 (2008) 309-312