Impact of Oligonucleotide Structure, Chemistry, and Delivery Method on in Vitro Cytotoxicity

Nucleic Acid Therapeutics

Volumn 27, Issue 1, 2017, Pages 11-22

  Janas, Maja M ^a   Jiang, Yongfeng ^a   Schlegel, Mark K ^a   Waldron, Scott ^a   Kuchimanchi, Satya ^a   Barros, Scott A ^a,b  

^a ALNYLAM PHARMACEUTICALS   (United States)

^b Sage Therapeutics Inc   (United States)

Author keywords

2 fluoro; Antisense; Cytotoxicity; Oligonucleotide; Phosphorothioate; siRNA

Indexed keywords

ASIALOGLYCOPROTEIN RECEPTOR; LIPOFECTAMINE; N ACETYLGALACTOSAMINE; OLIGONUCLEOTIDE; SINGLE STRANDED RNA; SMALL INTERFERING RNA; ANTISENSE OLIGONUCLEOTIDE; LIPID; NANOCONJUGATE; NUCLEAR PROTEIN; OLIGONUCLEOTIDE PHOSPHOROTHIOATE; RNA BINDING PROTEIN;

ARTICLE; CYTOTOXICITY TEST; DOUBLE STRANDED DNA BREAK; DRUG CYTOTOXICITY; DRUG DELIVERY SYSTEM; FEMALE; HELA CELL LINE; HEP-G2 CELL LINE; HUMAN; HUMAN CELL; IN VITRO STUDY; MEDICINAL CHEMISTRY; NUCLEIC ACID STRUCTURE; PRIORITY JOURNAL; CELL NUCLEUS; CELL SURVIVAL; CHEMISTRY; GENETIC TRANSFECTION; METABOLISM;

ASIALOGLYCOPROTEIN RECEPTOR; CELL NUCLEUS; CELL SURVIVAL; DNA BREAKS, DOUBLE-STRANDED; DRUG DELIVERY SYSTEMS; HELA CELLS; HEP G2 CELLS; HUMANS; LIPIDS; NANOCONJUGATES; NUCLEAR PROTEINS; OLIGORIBONUCLEOTIDES, ANTISENSE; PHOSPHOROTHIOATE OLIGONUCLEOTIDES; RNA, SMALL INTERFERING; RNA-BINDING PROTEINS; TRANSFECTION;

EID: 85011325677     PISSN: 21593337     EISSN: 21593345     Source Type: Journal    
DOI: 10.1089/nat.2016.0639     Document Type: Article

References (60)

1. Lundin KE, O Gissberg and C.I. Smith. (2015) Oligonucleotide therapies: the past and the present. Hum Gene Ther 26:475-485.
2. Wittrup A and J Lieberman. (2015). Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet 16:543-552.
3. Manoharan M. (2004). RNA interference and chemically modified small interfering RNAs. Curr Opin Chem Biol 8:570-579.
4. Bumcrot D, M Manoharan, V Koteliansky and DW Sah. (2006). RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2:711-719.
5. Eckstein F. (1985). Nucleoside phosphorothioates. Annu Rev Biochem 54:367-402.
6. Eckstein F. (2002). Developments in RNA chemistry, a personal view. Biochimie 84:841-848.
7. Eckstein F. (2000). Phosphorothioate oligodeoxynucleotides: what is their origin and what is unique about them Antisense Nucleic Acid Drug Dev 10:117-121.
8. Brown DA, SH Kang, SM Gryaznov, L DeDionisio, O Heidenreich, S Sullivan, X Xu and MI Nerenberg. (1994). Effect of phosphorothioate modification of oligodeoxynucleotides on specific protein binding. J Biol Chem 269: 26801-26805.
9. Mou TC and DM Gray. (2002). The high binding affinity of phosphorothioate-modified oligomers for Ff gene 5 protein is moderated by the addition of C-5 propyne or 2¢-O-methyl modifications. Nucleic Acids Res 30:749-758.
10. Geary RS, RZ Yu and AA Levin. (2001). Pharmacokinetics of phosphorothioate antisense oligodeoxynucleotides. Curr Opin Investig Drugs 2:562-573.
11. Watanabe TA, RS Geary and AA Levin. (2006). Plasma protein binding of an antisense oligonucleotide targeting human ICAM-1 (ISIS 2302). Oligonucleotides 16:169-180.
12. Bennett CF and EE Swayze. (2010). RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 50:259-293.
13. Lorenz P, T Misteli, BF Baker, CF Bennett and DL Spector. (2000). Nucleocytoplasmic shuttling: a novel in vivo property of antisense phosphorothioate oligodeoxynucleotides. Nucleic Acids Res 28:582-592.
14. Lorenz P, BF Baker, CF Bennett and DL Spector. (1998). Phosphorothioate antisense oligonucleotides induce the formation of nuclear bodies. Mol Biol Cell 9:1007-1023.
15. Slim G and MJ Gait. (1991). Configurationally defined phosphorothioate-containing oligoribonucleotides in the study of the mechanism of cleavage of hammerhead ribozymes. Nucleic Acids Res 19:1183-1188.
16. Spitzer S and F Eckstein. (1988). Inhibition of deoxyribonucleases by phosphorothioate groups in oligodeoxyribonucleotides. Nucleic Acids Res 16:11691-11704.
17. White AP, KK Reeves, E Snyder, J Farrell, JW Powell, V Mohan and RH Griffey. (1996). Hydration of singlestranded phosphodiester and phosphorothioate oligodeoxyribonucleotides. Nucleic Acids Res 24:3261-3266.
18. Kling J. (2010). Safety signal dampens reception for mipomersen antisense. Nat Biotechnol 28:295-297.
19. Henry SP, H Bolte, C Auletta and DJ Kornbrust. (1997). Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a four-week study in cynomolgus monkeys. Toxicology 120:145-155.
20. Stein CA, C Subasinghe, K Shinozuka and JS Cohen. (1988). Physicochemical properties of phosphorothioate oligodeoxynucleotides. Nucleic Acids Res 16:3209-3221.
21. Clark CL, PK Cecil, D Singh and DM Gray. (1997). CD, absorption and thermodynamic analysis of repeating dinucleotide DNA, RNA and hybrid duplexes [d/r(AC)]12.[d/r(GT/U)]12 and the influence of phosphorothioate substitution. Nucleic Acids Res 25:4098-4105.
22. Deleavey GF and MJ Damha. (2012). Designing chemically modified oligonucleotides for targeted gene silencing. Chem Biol 19:937-954.
23. Monia BP, EA Lesnik, C Gonzalez, WF Lima, D McGee, CJ Guinosso, AM Kawasaki, PD Cook, SM Freier. (1993). Evaluation of 2'-modified oligonucleotides containing 2'-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem 268:14514-14522.
24. Manoharan M. (1999). 2'-carbohydrate modifications in antisense oligonucleotide therapy: importance of conformation, configuration and conjugation. Biochim Biophys Acta 1489:117-130.
25. Pallan PS, EM Greene, PA Jicman, RK Pandey, M Manoharan, E Rozners and M Egli. (2011). Unexpected origins of the enhanced pairing affinity of 2'-fluoro-modified RNA. Nucleic Acids Res 39:3482-3495.
26. Watts JK, GF Deleavey and MJ Damha. (2008). Chemically modified siRNA: tools and applications. Drug Discov Today 13:842-855.
27. Shen W, XH Liang, H Sun and ST Crooke. (2015). 2'-Fluoro-modified phosphorothioate oligonucleotide can cause rapid degradation of P54nrb and PSF. Nucleic Acids Res 43:4569-4578.
28. Whitehead KA, JE Dahlman, RS Langer and DG Anderson. (2011). Silencing or stimulation siRNA delivery and the immune system. Annu Rev Chem Biomol Eng 2:77-96.
29. Rettig GR and MA Behlke. (2012). Progress toward in vivo use of siRNAs-II. Mol Ther 20:483-512.
30. Wahlestedt C, P Salmi, L Good, J Kela, T Johnsson, T Hokfelt, C Broberger, F Porreca, J Lai, K Ren, , et al. (2000). Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. Proc Natl Acad Sci USA 97:5633-5638.
31. Ten Asbroek AL, M van Groenigen, M Nooij and F Baas. (2002). The involvement of human ribonucleases H1 and H2 in the variation of response of cells to antisense phosphorothioate oligonucleotides. Eur J Biochem 269: 583-592.
32. Ward AJ, M Norrbom, S Chun, CF Bennett and F Rigo. (2014). Nonsense-mediated decay as a terminating mechanism for antisense oligonucleotides. Nucleic Acids Res 42:5871-5879.
33. Vickers TA, SM Freier, HH Bui, A Watt and ST Crooke. (2014). Targeting of repeated sequences unique to a gene results in significant increases in antisense oligonucleotide potency. PLoS One 9:e110615.
34. Leung AK, JM Calabrese and PA Sharp. (2006). Quantitative analysis of Argonaute protein reveals microRNAdependent localization to stress granules. Proc Natl Acad Sci USA 103:18125-18130.
35. Berman CL, SA Barros, SM Galloway, P Kasper, FB Oleson, CC Priestley, KS Sweder, MJ Schlosser and Z Sobol. (2016). OSWG recommendations for genotoxicity testing of novel oligonucleotide-based therapeutics. Nucleic Acid Ther 26:73-85.
36. Janas MM, Y Jiang, RG Duncan, AN Hayes, J Liu, PV Kasperkovitz, ME Placke and SA Barros. (2016). Exposure to siRNA-GalNAc conjugates in systems of the standard test battery for genotoxicity. Nucleic Acid Ther 26:363-371.
37. Nair JK, JL Willoughby, A Chan, K Charisse, MR Alam, Q Wang, M Hoekstra, P Kandasamy, AV Kel'in, S Milstein, , et al. (2014). Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAimediated gene silencing. J Am Chem Soc 136:16958-16961.
38. Burel SA, SR Han, HS Lee, DA Norris, BS Lee, T Machemer, SY Park, T Zhou, G He, Y Kim, , et al. (2013). Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys. Nucleic Acid Ther 23:213-227.
39. Prakash TP, MJ Graham, J Yu, R Carty, A Low, A Chappell, K Schmidt, C Zhao, M Aghajan, HF Murray, , et al. (2014). Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res 42:8796-8807.
40. Witzigmann D, L Quagliata, SH Schenk, C Quintavalle, LM Terracciano and J Huwyler. (2015). Variable asialoglycoproteinreceptor 1 expression in liver disease: implications for therapeutic intervention. Hepatol Res 46:686-696.
41. Capodici J, K Kariko and D Weissman. (2002). Inhibition of HIV-1 infection by small interfering RNA-mediated RNA interference. J Immunol 169:5196-5201.
42. Zhou J and JJ Rossi. (2011). Cell-specific aptamermediated targeted drug delivery. Oligonucleotides 21:1-10.
43. Layzer JM, AP McCaffrey, AK Tanner, Z Huang, MA Kay and BA Sullenger. (2004). In vivo activity of nucleaseresistant siRNAs. RNA 10:766-771.
44. Chiu YL and TM Rana. (2003). siRNA function in RNAi: a chemical modification analysis. RNA 9:1034-1048.
45. Ohrt T and Schwille P. (2008). siRNA modifications and sub-cellular localization: a question of intracellular transport Curr Pharm Des 14:3674-3685.
46. Marcusson EG, B Bhat, M Manoharan, CF Bennett and NM Dean. (1998). Phosphorothioate oligodeoxyribonucleotides dissociate from cationic lipids before entering the nucleus. Nucleic Acids Res 26:2016-2023.
47. Zelphati O and FC Szoka, Jr. (1996). Mechanism of oligonucleotide release from cationic liposomes. Proc Natl Acad Sci USA 93:11493-11498.
48. Bennett CF, MY Chiang, H Chan, JE Shoemaker and CK Mirabelli. (1992). Cationic lipids enhance cellular uptake and activity of phosphorothioate antisense oligonucleotides. Mol Pharmacol 41:1023-1033.
49. Fisher TL, T Terhorst, X Cao and RW Wagner. (1993). Intracellular disposition and metabolism of fluorescently-labeled unmodified and modified oligonucleotides microinjected into mammalian cells. Nucleic Acids Res 21:3857-3865.
50. Pichon C, I Freulon, P Midoux, R Mayer, M Monsigny and AC Roche. (1997). Cytosolic and nuclear delivery of oligonucleotides mediated by an amphiphilic anionic peptide. Antisense Nucleic Acid Drug Dev 7:335-343.
51. Castanotto D, M Lin, C Kowolik, L Wang, XQ Ren, HS Soifer, T Koch, BR Hansen, H Oerum, B Armstrong, , et al. (2015). A cytoplasmic pathway for gapmer antisense oligonucleotide-mediated gene silencing in mammalian cells. Nucleic Acids Res 43:9350-9361.
52. Zhao M, H Yang, X Jiang, W Zhou, B Zhu, Y Zeng, K Yao and C Ren. (2008). Lipofectamine RNAiMAX: an efficient siRNA transfection reagent in human embryonic stem cells. Mol Biotechnol 40:19-26.
53. Liang XH, W Shen, H Sun, TP Prakash and ST Crooke. (2014). TCP1 complex proteins interact with phosphorothioate oligonucleotides and can co-localize in oligonucleotideinduced nuclear bodies in mammalian cells. Nucleic Acids Res 42:7819-7832.
54. Jones S, DT Daley, NM Luscombe, HM Berman and JM Thornton. (2001). Protein-RNA interactions: a structural analysis. Nucleic Acids Res 29:943-954.
55. Shen W, XH Liang and ST Crooke. (2014). Phosphorothioate oligonucleotides can displace NEAT1 RNA and form nuclear paraspeckle-like structures. Nucleic Acids Res 42:8648-8662.
56. Pendergraff HM, AJ Debacker and JK Watts. (2016). Single-stranded silencing RNAs: hit rate and chemical modification. Nucleic Acid Ther 26:216-222.
57. Teplova M, G Minasov, V Tereshko, GB Inamati, PD Cook, M Manoharan and M Egli. (1999). Crystal structure and improved antisense properties of 2'-O-(2-methoxyethyl)-RNA. Nat Struct Biol 6:535-539.
58. Egli M, S Portmann and N Usman. (1996). RNA hydration: a detailed look. Biochemistry 35:8489-8494.
59. Harborth J, SM Elbashir, K Vandenburgh, H Manninga, SA Scaringe, Weber K and T Tuschl. (2003). Sequence, chemical, structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. Antisense Nucleic Acid Drug Dev 13:83-105.
60. Schwartz AL. (1991). Trafficking of asialoglycoproteins and the asialoglycoprotein receptor. Targeted Diagn Ther 4:3-39.