Recent advances in understanding of the immunological off-target effects of siRNA

Current Gene Therapy

Volumn 11, Issue 6, 2011, Pages 532-543

  Olejniczak, Marta ^a   Polak, Katarzyna ^a   Galka Marciniak, Paulina ^a   Krzyzosiak, Wlodzimierz J ^a  

^a INSTITUTE OF BIOORGANIC CHEMISTRY   (Poland)

Author keywords

Interferon response; Non specific effects; RNA interference; RNAimmuno; siRNA; Toxic effects

Indexed keywords

1,2 DIOLEOYL 3 TRIMETHYLAMMONIOPROPANE; CATIONIC LIPID; DHARMAFEST 124; DRUG VEHICLE; FUGENE; LIPID; LIPOFECTAMINE; LIPOSOME; NANOPARTICLE; OLIGOFECTAMINE; RETINOIC ACID INDUCIBLE PROTEIN I; SMALL INTERFERING RNA; TOLL LIKE RECEPTOR; UNCLASSIFIED DRUG;

APOPTOSIS; ARTICLE; CELL DIVISION; GENE SEQUENCE; GENE SILENCING; HUMAN; INNATE IMMUNITY; NONHUMAN; RNA INTERFERENCE; RNA STRUCTURE;

ANIMALS; DATABASES, FACTUAL; DRUG DELIVERY SYSTEMS; GENE SILENCING; HUMANS; RNA INTERFERENCE; RNA, SMALL INTERFERING;

EID: 82055208159     PISSN: 15665232     EISSN: 18755631     Source Type: Journal    
DOI: 10.2174/156652311798192770     Document Type: Article

References (135)

1. Lares MR, Rossi JJ, and Ouellet DL. RNAi and small interfering RNAs in human disease therapeutic applications. Trends Biotechnol 2010; 28(11): 570-9.
2. Lee CC and Chiang BL. RNA interference: new therapeutics in allergic diseases. Curr Gene Ther 2008; 8(4): 236-46.
3. Olejniczak M, Galka P, and Krzyzosiak WJ. Sequence-non-specific effects of RNA interference triggers and microRNA regulators. Nucleic Acids Res 2010; 38(1): 1-16.
4. Lewis BP, Burge CB, and Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120(1): 15-20.
5. Khan AA, Betel D, Miller ML, et al. Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs. Nat Biotechnol 2009; 27(6): 549-55.
6. Jackson AL and Linsley PS. Recognizing and avoiding siRNA offtarget effects for target identification and therapeutic application. Nature Reviews. Drug Discov 2010; 9(1): 57-67.
7. Samarajiwa SA, Forster S, Auchettl K, and Hertzog PJ. INTERFEROME: the database of interferon regulated genes. Nucleic Acids Research 2009; 37(Database issue): D852-7.
8. Pedersen IM, Cheng G, Wieland S, et al. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 2007; 449(7164): 919-22.
9. Wiesen JL and Tomasi TB. Dicer is regulated by cellular stresses and interferons. Mol Immunol 2009; 46(6): 1222-8.
10. Witwer KW, Sisk JM, Gama L, and Clements JE. MicroRNA regulation of IFN-beta protein expression: rapid and sensitive modulation of the innate immune response. J Immunol 2010; 184(5): 2369-76.
11. Gantier MP. New perspectives in MicroRNA regulation of innate immunity. Journal of Interferon & Cytokine Research: The Official J Internat Soc Interferon and Cytokine Res 2010; 30(5): 283-9.
12. Lunde BM, Moore C, and Varani G. RNA-binding proteins: modular design for efficient function. Nature reviews. Mol Cell Biol 2007; 8(6): 479-90.
13. Sakurai K, Amarzguioui M, Kim DH, et al. A role for human Dicer in pre-RISC loading of siRNAs. Nucleic Acids Res 2010.
14. Kok KH, Ng MH, Ching YP, and Jin DY. Human TRBP and PACT directly interact with each other and associate with dicer to facilitate the production of small interfering RNA. The J Biolog Chem 2007; 282(24): 17649-57.
15. Robb GB and Rana TM. RNA helicase A interacts with RISC in human cells and functions in RISC loading. Mol Cell 2007; 26(4): 523-37.
16. Sadler AJ, Latchoumanin O, Hawkes D, Mak J, and Williams BR. An antiviral response directed by PKR phosphorylation of the RNA helicase A. PLoS Pathog 2009; 5(2): e1000311.
17. Roberts WK, Clemens MJ, and Kerr IM. Interferon-induced inhibition of protein synthesis in L-cell extracts: an ATP-dependent step in the activation of an inhibitor by double-stranded RNA. Proc Natl Acad Sci USA 1976; 73(9): 3136-40.
18. Farrell PJ, Sen GC, Dubois MF, et al. Interferon action: two distinct pathways for inhibition of protein synthesis by doublestranded RNA. Proc Natl Acad Sci USA 1978; 75(12): 5893-7.
19. Sledz CA, Holko M, de Veer MJ, Silverman RH, and Williams BR. Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 2003; 5(9): 834-9.
20. Reynolds A, Anderson EM, Vermeulen A, et al. Induction of the interferon response by siRNA is cell type- and duplex lengthdependent. RNA 2006; 12(6): 988-93.
21. Kodym R, Kodym E, and Story MD. 2'-5'-Oligoadenylate synthetase is activated by a specific RNA sequence motif. Biochem Biophys Res Commun 2009; 388(2): 317-22.
22. Nallagatla SR, Hwang J, Toroney R, et al. 5'-triphosphatedependent activation of PKR by RNAs with short stem-loops. Science 2007; 318(5855): 1455-8.
23. McAllister CS and Samuel CE. The RNA-activated protein kinase enhances the induction of interferon-beta and apoptosis mediated by cytoplasmic RNA sensors. J Biolog Chem 2009; 284(3): 1644-51.
24. Schlee M and Hartmann G. The chase for the RIG-I ligand--recent advances. Molecular therapy: The J Am Soc Gene Ther 2010; 18(7): 1254-62.
25. Kang DC, Gopalkrishnan RV, Wu Q, et al. mda-5: An interferoninducible putative RNA helicase with double-stranded RNAdependent ATPase activity and melanoma growth-suppressive properties. Proc Natl Acad Sci USA 2002; 99(2): 637-42.
26. Malathi K, Dong B, Gale M, Jr., and Silverman RH. Small self- RNA generated by RNase L amplifies antiviral innate immunity. Nature 2007; 448(7155): 816-9.
27. Ablasser A, Bauernfeind F, Hartmann G, et al. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunol 2009; 10(10): 1065-72.
28. Chiu YH, Macmillan JB, and Chen ZJ. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 2009; 138(3): 576-91.
29. Choi MK, Wang Z, Ban T, et al. A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA. Proc Natl Acad Sci USA 2009; 106(42): 17870-5.
30. Mogensen TH and Paludan SR. Reading the viral signature by Toll-like receptors and other pattern recognition receptors. J Mol Med 2005; 83(3): 180-92.
31. Chang CI, Yoo JW, Hong SW, et al. Asymmetric shorter-duplex siRNA structures trigger efficient gene silencing with reduced nonspecific effects. Molecular Therapy: The J Am Soc Gene Ther 2009; 17(4): 725-32.
32. Bolcato-Bellemin AL, Bonnet ME, Creusat G, Erbacher P, and Behr JP. Sticky overhangs enhance siRNA-mediated gene silencing. Proc Natl Acad Sci USA 2007; 104(41): 16050-5.
33. Bramsen JB, Laursen MB, Damgaard CK, et al. Improved silencing properties using small internally segmented interfering RNAs. Nucleic Acids Res 2007; 35(17): 5886-97.
34. Sibley CR, Seow Y, and Wood MJ. Novel RNA-based strategies for therapeutic gene silencing. Molecular therapy: The J Am Soc Gene Ther 2010; 18(3): 466-76.
35. Marques JT, Devosse T, Wang D, et al. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat Biotechnol 2006; 24(5): 559-65.
36. Bonnet ME, Erbacher P, and Bolcato-Bellemin AL. Systemic delivery of DNA or siRNA mediated by linear polyethylenimine (L-PEI) does not induce an inflammatory response. Pharm Res 2008; 25(12): 2972-82.
37. Kleinman ME, Yamada K, Takeda A, et al. Sequence- and targetindependent angiogenesis suppression by siRNA via TLR3. Nature 2008; 452(7187): 591-7.
38. Cornelie S, Hoebeke J, Schacht AM, et al. Direct evidence that toll-like receptor 9 (TLR9) functionally binds plasmid DNA by specific cytosine-phosphate-guanine motif recognition. The J Biolog Chem 2004; 279(15): 15124-9.
39. Takaoka A, Wang Z, Choi MK, et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 2007; 448(7152): 501-5.
40. Grimm D, Streetz KL, Jopling CL, et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 2006; 441(7092): 537-41.
41. Castanotto D, Sakurai K, Lingeman R, et al. Combinatorial delivery of small interfering RNAs reduces RNAi efficacy by selective incorporation into RISC. Nucleic Acids Res 2007; 35(15): 5154-64.
42. Boudreau RL, Martins I, and Davidson BL. Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Molecular Therapy: The J Am Soc Gene Ther 2009; 17(1): 169-75.
43. Bos TJ, De Bruyne E, Heirman C, and Vanderkerken K. In search of the most suitable lentiviral shRNA system. Curr Gene Ther 2009; 9(3): 192-211.
44. Schlee M, Roth A, Hornung V, et al. Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity 2009; 31(1): 25-34.
45. Schmidt A, Schwerd T, Hamm W, et al. 5'-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I. Proc Natl Acad Sci USA 2009; 106(29): 12067-72.
46. Akashi H, Miyagishi M, Yokota T, et al. Escape from the interferon response associated with RNA interference using vectors that encode long modified hairpin-RNA. Mol bioSystems 2005; 1(5-6): 382-90.
47. Zhang X and Zeng Y. The terminal loop region controls microRNA processing by Drosha and Dicer. Nucleic Acids Res 2010; 38(21): 7689-97.
48. Cullen BR. Enhancing and confirming the specificity of RNAi experiments. Nat Methods 2006; 3(9): 677-81.
49. Hornung V, Guenthner-Biller M, Bourquin C, et al. Sequencespecific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 2005; 11(3): 263-70.
50. Judge AD, Sood V, Shaw JR, et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol 2005; 23(4): 457-62.
51. Sioud M. Single-stranded small interfering RNA are more immunostimulatory than their double-stranded counterparts: a central role for 2'-hydroxyl uridines in immune responses. Eur J Immunol 2006; 36(5): 1222-30.
52. Diebold SS, Massacrier C, Akira S, et al. Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides. Eur J Immunol 2006; 36(12): 3256-67.
53. Forsbach A, Nemorin JG, Montino C, et al. Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses. J Immunol 2008; 180(6): 3729-38.
54. Gantier MP, Tong S, Behlke MA, et al. TLR7 is involved in sequence-specific sensing of single-stranded RNAs in human macrophages. J Immunol 2008; 180(4): 2117-24.
55. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, and Iggo R. Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet 2003; 34(3): 263-4.
56. Stewart CK, Li J, and Golovan SP. Adverse effects induced by short hairpin RNA expression in porcine fetal fibroblasts. Biochem Biophys Res Commun 2008; 370(1): 113-7.
57. Liu YP, von Eije KJ, Schopman NC, et al. Combinatorial RNAi against HIV-1 using extended short hairpin RNAs. Molecular Therapy: The J Am Soc Gene Ther 2009; 17(10): 1712-23.
58. Kenworthy R, Lambert D, Yang F, et al. Short-hairpin RNAs delivered by lentiviral vector transduction trigger RIG-I-mediated IFN activation. Nucleic Acids Res 2009; 37(19): 6587-99.
59. Robbins MA, Li M, Leung I, et al. Stable expression of shRNAs in human CD34+ progenitor cells can avoid induction of interferon responses to siRNAs in vitro. Nat Biotechnol 2006; 24(5): 566-71.
60. Bramsen JB, Pakula MM, Hansen TB, et al. A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects. Nucleic Acids Res 2010; 38(17): 5761-73.
61. Judge AD, Bola G, Lee AC, and MacLachlan I. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Molecular Therapy: The J Am Soc Gene Ther 2006; 13(3): 494-505.
62. Shukla S, Sumaria CS, and Pradeepkumar PI. Exploring chemical modifications for siRNA therapeutics: a structural and functional outlook. ChemMedChem 2010; 5(3): 328-49.
63. Chernolovskaya EL and Zenkova MA. Chemical modification of siRNA. Curr Opin Mol Ther 2010; 12(2): 158-67.
64. Braasch DA, Jensen S, Liu Y, et al. RNA interference in mammalian cells by chemically-modified RNA. Biochemistry 2003; 42(26): 7967-75.
65. Li ZY, Mao H, Kallick DA, and Gorenstein DG. The effects of thiophosphate substitutions on native siRNA gene silencing. Biochem Biophys Res Commun 2005; 329(3): 1026-30.
66. Sioud M, Furset G, and Cekaite L. Suppression of immunostimulatory siRNA-driven innate immune activation by 2'- modified RNAs. Biochem Biophys Res Commun 2007; 361(1): 122-6.
67. Collingwood MA, Rose SD, Huang L, et al. Chemical modification patterns compatible with high potency dicer-substrate small interfering RNAs. Oligonucleotides 2008; 18(2): 187-200.
68. Zamanian-Daryoush M, Marques JT, Gantier MP, et al. Determinants of cytokine induction by small interfering RNA in human peripheral blood mononuclear cells. Journal of Interferon & Cytokine Research: The Off J Internat Soc Interferon and Cytokine Res 2008; 28(4): 221-33.
69. Hamm S, Latz E, Hangel D, et al. Alternating 2'-O-ribose methylation is a universal approach for generating non-stimulatory siRNA by acting as TLR7 antagonist. Immunobiology 2010; 215(7): 559-69.
70. Judge AD, Robbins M, Tavakoli I, et al. Confirming the RNAimediated mechanism of action of siRNA-based cancer therapeutics in mice. The J Clin Investig 2009; 119(3): 661-73.
71. Eberle F, Giessler K, Deck C, et al. Modifications in small interfering RNA that separate immunostimulation from RNA interference. J Immunol 2008; 180(5): 3229-37.
72. Mook OR, Baas F, de Wissel MB, and Fluiter K. Evaluation of locked nucleic acid-modified small interfering RNA in vitro and in vivo. Mol Cancer Ther 2007; 6(3): 833-43.
73. Deleavey GF, Watts JK, Alain T, et al. Synergistic effects between analogs of DNA and RNA improve the potency of siRNAmediated gene silencing. Nucleic Acids Res 2010; 38(13): 4547-57.
74. Kariko K, Buckstein M, Ni H, and Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005; 23(2): 165-75.
75. Hornung V, Ellegast J, Kim S, et al. 5'-Triphosphate RNA is the ligand for RIG-I. Science 2006; 314(5801): 994-7.
76. Vitali P and Scadden AD. Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis. Nat Struct Mol Biol 2010; 17(9): 1043-50.
77. Juliano R, Alam MR, Dixit V, and Kang H. Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Res 2008; 36(12): 4158-71.
78. Tseng YC, Mozumdar S, and Huang L. Lipid-based systemic delivery of siRNA. Adv Drug Deliv Rev 2009; 61(9): 721-31.
79. Shim MS and Kwon YJ. Efficient and targeted delivery of siRNA in vivo. The FEBS J 2010; 277(23): 4814-27.
80. Guo J, Fisher KA, Darcy R, Cryan JF, and O'Driscoll C. Therapeutic targeting in the silent era: advances in non-viral siRNA delivery. Mol bioSystems 2010; 6(7): 1143-61.
81. Zimmermann TS, Lee AC, Akinc A, et al. RNAi-mediated gene silencing in non-human primates. Nature 2006; 441(7089): 111-4.
82. Pauls E, Senserrich J, Bofill M, Clotet B, and Este JA. Induction of interleukins IL-6 and IL-8 by siRNA. Clin Exper Immunol 2007; 147(1): 189-96.
83. Abrams MT, Koser ML, Seitzer J, et al. Evaluation of efficacy, biodistribution, and inflammation for a potent siRNA nanoparticle: effect of dexamethasone co-treatment. Molecular Therapy: The J Am Soc Gene Ther 2010; 18(1): 171-80.
84. Heidel JD, Hu S, Liu XF, Triche TJ, and Davis ME. Lack of interferon response in animals to naked siRNAs. Nat Biotechnol 2004; 22(12): 1579-82.
85. Ma Z, Li J, He F, et al. Cationic lipids enhance siRNA-mediated interferon response in mice. Biochem Biophys Res Commun 2005; 330(3): 755-9.
86. Yokota T, Iijima S, Kubodera T, et al. Efficient regulation of viral replication by siRNA in a non-human primate surrogate model for hepatitis C. Biochem Biophys Res Commun 2007; 361(2): 294-300.
87. Kornek M, Lukacs-Kornek V, Limmer A, et al. 1,2-dioleoyl-3- trimethylammonium-propane (DOTAP)-formulated, immunestimulatory vascular endothelial growth factor a small interfering RNA (siRNA) increases antitumoral efficacy in murine orthotopic hepatocellular carcinoma with liver fibrosis. Mol Med 2008; 14(7- 8): 365-73.
88. Mescalchin A, Detzer A, Wecke M, et al. Cellular uptake and intracellular release are major obstacles to the therapeutic application of siRNA: novel options by phosphorothioatestimulated delivery. Exp Opin Biolog Ther 2007; 7(10): 1531-8.
89. Sioud M. Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. J Mol Biol 2005; 348(5): 1079-90.
90. Ablasser A, Poeck H, Anz D, et al. Selection of molecular structure and delivery of RNA oligonucleotides to activate TLR7 versus TLR8 and to induce high amounts of IL-12p70 in primary human monocytes. J Immunol 2009; 182(11): 6824-33.
91. Yoo JW, Hong SW, Kim S, and Lee DK. Inflammatory cytokine induction by siRNAs is cell type- and transfection reagent-specific. Biochem Biophys Res Commun 2006; 347(4): 1053-8.
92. Kim SS, Ye C, Kumar P, et al. Targeted delivery of siRNA to macrophages for anti-inflammatory treatment. Molecular Therapy: The J Am Soc Gene Ther 2010; 18(5): 993-1001.
93. Landen CN, Jr., Goodman B, Katre AA, et al. Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Mol Cancer Ther 2010; 9(12): 3186-99.
94. Peer D, Park EJ, Morishita Y, Carman CV, and Shimaoka M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science 2008; 319(5863): 627-30.
95. Vivas-Mejia PE, Rodriguez-Aguayo C, Han HD, et al. Silencing Survivin Splice Variant 2B Leads to Antitumor Activity in Taxane- Resistant Ovarian Cancer. Clinical Cancer Research: An off J Am Assoc Cancer Res 2011.
96. Dufes C, Keith WN, Bilsland A, et al. Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors. Cancer Res 2005; 65(18): 8079-84.
97. Beyerle A, Hobel S, Czubayko F, et al. In vitro cytotoxic and immunomodulatory profiling of low molecular weight polyethylenimines for pulmonary application. Toxicology in vitro: an international journal published in association with BIBRA 2009; 23(3): 500-8.
98. Chen H, Li P, Yin Y, et al. The promotion of type 1 T helper cell responses to cationic polymers in vivo via toll-like receptor-4 mediated IL-12 secretion. Biomaterials 2010; 31(32): 8172-80.
99. Kedmi R, Ben-Arie N, and Peer D. The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation. Biomaterials 2010; 31(26): 6867-75.
100. Cubillos-Ruiz JR, Engle X, Scarlett UK, et al. Polyethyleniminebased siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. The J Clin Invest 2009; 119(8): 2231-44.
101. Omidi Y, Hollins AJ, Benboubetra M, et al. Toxicogenomics of non-viral vectors for gene therapy: a microarray study of lipofectinand oligofectamine-induced gene expression changes in human epithelial cells. J Drug Target 2003; 11(6): 311-23.
102. Hollins AJ, Omidi Y, Benter IF, and Akhtar S. Toxicogenomics of drug delivery systems: Exploiting delivery system-induced changes in target gene expression to enhance siRNA activity. J Drug Target 2007; 15(1): 83-8.
103. Tagami T, Hirose K, Barichello JM, Ishida T, and Kiwada H. Global gene expression profiling in cultured cells is strongly influenced by treatment with siRNA-cationic liposome complexes. Pharm Res 2008; 25(11): 2497-504.
104. Lacaze P, Raza S, Sing G, et al. Combined genome-wide expression profiling and targeted RNA interference in primary mouse macrophages reveals perturbation of transcriptional networks associated with interferon signalling. BMC Genomics 2009; 10: 372.
105. Merkel OM, Beyerle A, Beckmann BM, et al. Polymer-related offtarget effects in non-viral siRNA delivery. Biomaterials 2011; 32(9): 2388-98.
106. Morrissey DV, Lockridge JA, Shaw L, et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 2005; 23(8): 1002-7.
107. Alvarez R, Elbashir S, Borland T, et al. RNA interferencemediated silencing of the respiratory syncytial virus nucleocapsid defines a potent antiviral strategy. Antimicrob Agents Chemother 2009; 53(9): 3952-62.
108. Tompkins SM, Lo CY, Tumpey TM, and Epstein SL. Protection against lethal influenza virus challenge by RNA interference in vivo. Proc Natl Acad Sci USA 2004; 101(23): 8682-6.
109. Ge Q, Filip L, Bai A, et al. Inhibition of influenza virus production in virus-infected mice by RNA interference. Proc Natl Acad Sci USA 2004; 101(23): 8676-81.
110. Palliser D, Chowdhury D, Wang QY, et al. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature 2006; 439(7072): 89-94.
111. Nguyen DN, Chen SC, Lu J, et al. Drug delivery-mediated control of RNA immunostimulation. Mol Ther: The J Am Soc Gene Ther 2009; 17(9): 1555-62.
112. Robbins M, Judge A, Ambegia E, et al. Misinterpreting the therapeutic effects of small interfering RNA caused by immune stimulation. Hum Gene Ther 2008; 19(10): 991-9.
113. Tschuch C, Schulz A, Pscherer A, et al. Off-target effects of siRNA specific for GFP. BMC Mol Biol 2008; 9: 60.
114. Baum P, Fundel-Clemens K, Kreuz S, et al. Off-target analysis of control siRNA molecules reveals important differences in the cytokine profile and inflammation response of human fibroblasts. Oligonucleotides 2010; 20(1): 17-26.
115. Hobel S, Koburger I, John M, et al. Polyethylenimine/small interfering RNA-mediated knockdown of vascular endothelial growth factor in vivo exerts anti-tumor effects synergistically with Bevacizumab. The J Gene Med 2010; 12(3): 287-300.
116. Ashikari M, Tokoro M, Itaya M, Nozaki M, and Ogura Y. Suppression of laser-induced choroidal neovascularization by nontargeted siRNA. Investig Ophthal Vis Sci 2010; 51(7): 3820-4.
117. Gu L, Chen H, Tuo J, Gao X, and Chen L. Inhibition of experimental choroidal neovascularization in mice by anti- VEGFA/VEGFR2 or non-specific siRNA. Exper Eye Res 2010; 91(3): 433-9.
118. Berge M, Bonnin P, Sulpice E, et al. Small interfering RNAs induce target-independent inhibition of tumor growth and vasculature remodeling in a mouse model of hepatocellular carcinoma. The Am J Pathol 2010; 177(6): 3192-201.
119. Poeck H, Besch R, Maihoefer C, et al. 5'-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat Med 2008; 14(11): 1256-63.
120. Anz D, Koelzer VH, Moder S, et al. Immunostimulatory RNA blocks suppression by regulatory T cells. J Immunol 2010; 184(2): 939-46.
121. Bourquin C, Wurzenberger C, Heidegger S, et al. Delivery of immunostimulatory RNA oligonucleotides by gelatin nanoparticles triggers an efficient antitumoral response. J Immunother 2010; 33(9): 935-44.
122. Bourquin C, Schmidt L, Lanz AL, et al. Immunostimulatory RNA oligonucleotides induce an effective antitumoral NK cell response through the TLR7. J Immunol 2009; 183(10): 6078-86.
123. Gantier MP, Tong S, Behlke MA, et al. Rational design of immunostimulatory siRNAs. Molecular Therapy: The J Am Soc Gene Ther 2010; 18(4): 785-95.
124. Chen LL, Yang L, and Carmichael GG. Molecular basis for an attenuated cytoplasmic dsRNA response in human embryonic stem cells. Cell Cycle 2010; 9(17): 3552-64.
125. Gorina R, Santalucia T, Petegnief V, et al. Astrocytes are very sensitive to develop innate immune responses to lipid-carried short interfering RNA. Glia 2009; 57(1): 93-107.
126. Lafon M, Megret F, Lafage M, and Prehaud C. The innate immune facet of brain: human neurons express TLR-3 and sense viral dsRNA. J Mol Neurosci: MN 2006; 29(3): 185-94.
127. Muzio M, Bosisio D, Polentarutti N, et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 2000; 164(11): 5998-6004.
128. Perrot I, Deauvieau F, Massacrier C, et al. TLR3 and Rig-like receptor on myeloid dendritic cells and Rig-like receptor on human NK cells are both mandatory for production of IFN-gamma in response to double-stranded RNA. J Immunol 2010; 185(4): 2080-8.
129. Li K, Chen Z, Kato N, Gale M, Jr., and Lemon SM. Distinct poly(IC) and virus-activated signaling pathways leading to interferonbeta production in hepatocytes. The J Biolog Chem 2005; 280(17): 16739-47.
130. Puthenveetil S, Whitby L, Ren J, et al. Controlling activation of the RNA-dependent protein kinase by siRNAs using site-specific chemical modification. Nucleic Acids Res 2006; 34(17): 4900-11.
131. Sen GC and Sarkar SN. Transcriptional signaling by doublestranded RNA: role of TLR3. Cytokine & Growth Factor Rev 2005; 16(1): 1-14.
132. Cho WG, Albuquerque RJ, Kleinman ME, et al. Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth. Proc Nat Acad Sci USA 2009; 106(17): 7137-42.
133. Gantier MP and Williams BR. Monitoring innate immune recruitment by siRNAs in mammalian cells. Methods Mol Biol 2010; 623: 21-33.
134. Read ML, Mir S, Spice R, et al. Profiling RNA interference (RNAi)-mediated toxicity in neural cultures for effective short interfering RNA design. J Gene Med 2009; 11(6): 523-34.
135. Chang CI, Kang HS, Ban C, Kim S, and Lee DK. Dual-target gene silencing by using long, synthetic siRNA duplexes without triggering antiviral responses. Mol Cells 2009; 27(6): 689-95.