1932

Abstract

Recent studies have led to a greater appreciation of the diverse roles RNAs play in maintaining normal cellular function and how they contribute to disease pathology, broadening the number of potential therapeutic targets. Antisense oligonucleotides are the most direct means to target RNA in a selective manner and have become an established platform technology for drug discovery. There are multiple molecular mechanisms by which antisense oligonucleotides can be used to modulate RNAs in cells, including promoting the degradation of the targeted RNA or modulating RNA function without degradation. Antisense drugs utilizing various antisense mechanisms are demonstrating therapeutic potential for the treatment of a broad variety of diseases. This review focuses on some of the advances that have taken place in translating antisense technology from the bench to the clinic.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010716-104846
2017-01-06
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/57/1/annurev-pharmtox-010716-104846.html?itemId=/content/journals/10.1146/annurev-pharmtox-010716-104846&mimeType=html&fmt=ahah

Literature Cited

  1. Rader DJ, Kastelein JJ. 1.  2014. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 129:1022–32 [Google Scholar]
  2. Bennett CF, Swayze EE. 2.  2010. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Ann. Rev. Pharmacol. Toxicol. 50:259–93 [Google Scholar]
  3. Bennett CF, Swayze E, Henry S, Geary R. 3.  2015. Antisense oligonucleotide-based therapeutics. Gene and Cell Therapy: Therapeutic Mechanisms and Strategies NS Templeton 467–92 Boca Raton, FL: CRC Press [Google Scholar]
  4. Akinc A, Betterncourt BR, Maier MA. 4.  2015. Development of RNAi therapeutics. Gene and Cell Therapy: Therapeutic Mechanisms and Strategies NS Templeton 493–520 Boca Raton, FL: CRC Press [Google Scholar]
  5. Soto-Pantoja DR, Isenberg JS, Roberts DD. 5.  2015. Therapeutic applications of morpholino oligonucleotides. Gene and Cell Therapy: Therapeutic Mechanisms and Strategies NS Templeton 521–41 Boca Raton, FL: CRC Press [Google Scholar]
  6. Lima WF, Wu H, Crooke ST. 6.  2008. The RNase H mechanism. Antisense Drug Technology: Principles, Strategies, and Applications ST Crooke 47–74 Boca Raton, FL: CRC Press [Google Scholar]
  7. Esau C, Davis S, Murray SF, Yu XX, Pandey SK. 7.  et al. 2006. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 3:87–98 [Google Scholar]
  8. Rotllan N, Ramírez CM, Aryal B, Esau CC, Fernández-Hernando C. 8.  2013. Therapeutic silencing of microRNA-33 inhibits the progression of atherosclerosis in Ldlr/− mice—brief report. Arterioscler. Thromb. Vasc. Biol. 33:1973–77 [Google Scholar]
  9. Liang X-H, Shen W, Sun H, Migawa MT, Vickers TA, Crooker ST. 9.  2016. Translation efficiency of mRNAs is increased by antisense oligonucleotides targeting upstream open reading frames. Nat. Biotechnol. 34:875–880 [Google Scholar]
  10. Stein CA, Subasinghe C, Shinozuka K, Cohen JS. 10.  1988. Physicochemical properties of phosphorothioate oligodeoxynucleotides. Nucleic Acids Res 16:3209–21 [Google Scholar]
  11. Gryaznov S, Skorski T, Cucco C, Nieborowska-Skorska M, Chiu CY. 11.  et al. 1996. Oligonucleotide N3′→P5′ phosphoramidates as antisense agents. Nucleic Acids Res. 24:1508–14 [Google Scholar]
  12. Herdewijn P. 12.  2000. Heterocyclic modifications of oligonucleotides and antisense technology. Antisense Nucleic Acid Drug Dev. 10:297–310 [Google Scholar]
  13. Freier SM, Altmann K-H. 13.  1997. The ups and downs of nucleic acid duplex stability: structure-stability studies on chemically-modified DNA:RNA duplexes. Nucleic Acids Res. 25:4429–43 [Google Scholar]
  14. Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA. 14.  et al. 1995. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–49 [Google Scholar]
  15. Froehler BC, Wadwani S, Terhorst TJ, Gerrard SR. 15.  1992. Oligodeoxynucleotides containing C-5 propyne analogs of 2′-deoxyuridine and 2′-deoxycytidine. Tetrahedron Lett. 33:5307–10 [Google Scholar]
  16. Shen L, Siwkowski A, Wancewicz EV, Lesnik EA, Butler M. 16.  et al. 2003. Evaluation of C-5 propynyl pyrmidine-containing oligonucleotides in vitro and in vivo. Antisense Nucleic Acid Drug Dev. 13:129–42 [Google Scholar]
  17. Monia BP, Lesnik EA, Gonzalez C, Lima WF, McGee D. 17.  et al. 1993. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J. Biol. Chem. 268:14514–22 [Google Scholar]
  18. Goel S, Desai K, Macapinlac M, Wadler S, Goldberg G. 18.  et al. 2006. A phase I safety and dose escalation trial of docetaxel combined with GEM®231, a second generation antisense oligonucleotide targeting protein kinase A R1α in patients with advanced solid cancers. Investig. New Drugs 24:125–34 [Google Scholar]
  19. Voit T, Topaloglu H, Straub V, Muntoni F, Deconinck N. 19.  et al. 2014. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol 13:987–96 [Google Scholar]
  20. Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R. 20.  et al. 2004. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432:173–78 [Google Scholar]
  21. Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D. 21.  et al. 2006. RNAi-mediated gene silencing in non-human primates. Nature 441:111–14 [Google Scholar]
  22. Jackson AL, Burchard J, Leake D, Reynolds A, Schelter J. 22.  et al. 2006. Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. RNA 12:1197–205 [Google Scholar]
  23. Allerson CR, Sioufi N, Jarres R, Prakash TP, Naik N. 23.  et al. 2005. Fully 2′-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. J. Med. Chem. 48:901–4 [Google Scholar]
  24. Nair JK, Willoughby JLS, Chan A, Charisse K, Alam MR. 24.  et al. 2014. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136:16958–61 [Google Scholar]
  25. Henry S, Stecker K, Brooks D, Monteith D, Conklin B, Bennett CF. 25.  2000. Chemically modified oligonucleotides exhibit decreased immune stimulation in mice. J. Pharmacol. Exp. Ther. 292:468–79 [Google Scholar]
  26. Crooke ST, Geary RS. 26.  2013. Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B. Br. J. Clin. Pharmacol. 76:269–76 [Google Scholar]
  27. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J. 27.  et al. 2016. Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology 86:890–97 [Google Scholar]
  28. Rigo F, Chun SJ, Norris DA, Hung G, Lee S. 28.  et al. 2014. Pharmacology of a central nervous system delivered 2′-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. J. Pharmacol. Exp. Ther. 350:46–55 [Google Scholar]
  29. Ackermann EJ, Guo S, Benson MD, Booten S, Freier S. 29.  et al. 2016. Suppressing transthyretin production in mice, monkeys and humans using 2nd-generation antisense oligonucleotides. Amyloid. 23:148–57 [Google Scholar]
  30. Lima WF, Prakash TP, Murray HM, Kinberger GA, Li W. 30.  et al. 2012. Single-stranded siRNAs activate RNAi in animals. Cell 150:883–94 [Google Scholar]
  31. Obika S, Nanbu D, Hari Y, Morio K-I, In Y. 31.  et al. 1997. Synthesis of 2′-O,4′-C-methyleneuridine and -cytidine. Novel bicyclic nucleosides having a fixed C3, -endo sugar puckering. Tetrahedron Lett. 38:8735–38 [Google Scholar]
  32. Wengel J. 32.  1999. Synthesis of 3′-C- and 4′-C-branched oligodeoxynucleotides and the development of locked nucleic acid (LNA). Acc. Chem. Res. 32:301–10 [Google Scholar]
  33. Kurreck J, Wyszko E, Gillen C, Erdmann VA. 33.  2002. Design of antisense oligonucleotides stabilized by locked nucleic acids. Nucleic Acids Res. 30:1911–18 [Google Scholar]
  34. Seth PP, Swayze EE. 34.  2014. Unnatural nucleoside analogs for antisense therapy. Natural Products in Medicinal Chemistry S Hanessian 403–40 Weinheim, Ger.: Wiley-VCH [Google Scholar]
  35. Fluiter K, Frieden M, Vreijling J, Rosenbohm C, De Wissel MB. 35.  et al. 2005. On the in vitro and in vivo properties of four locked nucleic acid nucleotides incorporated into an anti-H-Ras antisense oligonucleotide. ChemBioChem 6:1104–9 [Google Scholar]
  36. Morita K, Hasegawa C, Kaneko M, Tsutsumi S, Sone J. 36.  et al. 2002. 2′-O,4′-C-ethylene-bridged nucleic acids (ENA): highly nuclease-resistant and thermodynamically stable oligonucleotides for antisense drug. Bioorg. Med. Chem. Lett. 12:73–76 [Google Scholar]
  37. Burdick AD, Sciabola S, Mantena SR, Hollingshead BD, Stanton R. 37.  et al. 2014. Sequence motifs associated with hepatotoxicity of locked nucleic acid–modified antisense oligonucleotides. Nucleic Acids Res. 42:4882–489 [Google Scholar]
  38. Swayze EE, Siwkowski AM, Wancewicz EV, Migawa MT, Wyrzykiewicz TK. 38.  et al. 2007. Antisense oligonucleotides containing locked nucleic acid (LNA) improve potency but cause significant hepatotoxicity in animals. Nucleic Acids Res. 35:687–700 [Google Scholar]
  39. Prakash TP, Siwkowski A, Allerson CR, Migawa MT, Lee S. 39.  et al. 2010. Antisense oligonucleotides containing conformationally constrained 2′,4′-(N-methoxy)aminomethylene and 2′,4′-aminooxymethylene and 2′-O,4′-C-aminomethylene bridged nucleoside analogues show improved potency in animal models. J. Med. Chem. 53:1636–50 [Google Scholar]
  40. Seth PP, Jazayeri A, Yu J, Allerson CR, Bhat B, Swayze EE. 40.  2012. Structure activity relationships of α-l-LNA modified phosphorothioate gapmer antisense oligonucleotides in animals. Mol. Ther. Nucleic Acids 1:e47 [Google Scholar]
  41. Pallan PS, Allerson CR, Berdeja A, Seth PP, Swayze EE. 41.  et al. 2012. Structure and nuclease resistance of 2′,4′-constrained 2′-O-methoxyethyl (cMOE) and 2′-O-ethyl (cEt) modified DNAs. Chem. Commun. 48:8195–97 [Google Scholar]
  42. Egli M, Pallan PS, Allerson CR, Prakash TP, Berdeja A. 42.  et al. 2011. Synthesis, improved antisense activity and structural rationale for the divergent RNA affinities of 3′-fluoro hexitol nucleic acid (FHNA and Ara-FHNA) modified oligonucleotides. J. Am. Chem. Soc. 133:16642–49 [Google Scholar]
  43. Seth PP, Allerson CR, Siwkowski A, Vasquez G, Berdeja A. 43.  et al. 2010. Configuration of the 5′-methyl group modulates the biophysical and biological properties of locked nucleic acid (LNA) oligonucleotides. J. Med. Chem. 53:8309–18 [Google Scholar]
  44. Burel SA, Han SR, Lee HS, Norris DA, Lee BS. 44.  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 23:213–27 [Google Scholar]
  45. Pandey SK, Wheeler TM, Justice SL, Kim A, Younis H. 45.  et al. 2015. Identification and characterization of modified antisense oligonucleotides targeting DMPK in mice and nonhuman primates for the treatment of myotonic dystrophy type 1. J. Pharmacol. Exp. Ther. 355:329–40 [Google Scholar]
  46. Crooke ST, Graham MJ, Zuckerman JE, Brooks D, Conklin BS. 46.  et al. 1996. Pharmacokinetic properties of several novel oligonucleotide analogs in mice. J. Pharmacol. Exp. Ther. 277:923–37 [Google Scholar]
  47. Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T. 47.  et al. 2005. Silencing of microRNAs in vivo with “antagomirs.”. Nature 438:685–89 [Google Scholar]
  48. Herbert BS, Gellert GC, Hochreiter A, Pongracz K, Wright WE. 48.  et al. 2005. Lipid modification of GRN163, an N3′ → P5′ thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene 24:5262–68 [Google Scholar]
  49. Nishina K, Unno T, Uno Y, Kubodera T, Kanouchi T. 49.  et al. 2008. Efficient in vivo delivery of siRNA to the liver by conjugation of α-tocopherol. Mol. Ther. 16:734–40 [Google Scholar]
  50. Nishina K, Piao W, Yoshida-Tanaka K, Sujino Y, Nishina T. 50.  et al. 2015. DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing. Nat. Commun. 6:7969 [Google Scholar]
  51. Prakash TP, Graham MJ, Yu J, Carty R, Low A. 51.  et al. 2014. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 42:8796–807 [Google Scholar]
  52. Prakash TP, Yu J, Migawa MT, Kinberger GA, Wan WB. 52.  et al. 2016. Comprehensive structure-activity relationship of triantennary N-acetylgalactosamine conjugated antisense oligonucleotides for targeted delivery to hepatocytes. J. Med. Chem. 59:2718–33 [Google Scholar]
  53. Geary RS, Norris D, Yu R, Bennett CF. 53.  2015. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv. Drug Deliv. Rev. 87:46–51 [Google Scholar]
  54. Levin AA, Yu RZ, Geary RS. 54.  2008. Basic principles of the pharmacokinetics of antisense oligonucleotide drugs. Antisense Drug Technology: Principles, Strategies, and Applications ST Crooke 183–216 Boca Raton, FL: CRC Press [Google Scholar]
  55. Koller E, Vincent TM, Chappell A, De S, Manoharan M, Bennett CF. 55.  2011. Mechanisms of single-stranded phosphorothioate modified antisense oligonucleotide accumulation in hepatocytes. Nucleic Acids Res. 39:4795–807 [Google Scholar]
  56. Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM. 56.  et al. 2012. Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron 74:1031–44 [Google Scholar]
  57. Yu RZ, Lemonidis KM, Graham MJ, Matson JE, Crooke RM. 57.  et al. 2009. Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100. Biochem. Pharmacol. 77:910–19 [Google Scholar]
  58. Hung G, Xiao X, Peralta R, Bhattacharjee G, Murray S. 58.  et al. 2013. Characterization of target mRNA reduction through in situ RNA hybridization in multiple organ systems following systemic antisense treatment in animals. Nucleic Acid Ther 23:369–78 [Google Scholar]
  59. Raoof AA, Chiu P, Ramtoola Z, Cumming IK, Teng CL. 59.  et al. 2004. Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate. J. Pharm. Sci. 93:1431–39 [Google Scholar]
  60. Templin MV, Levin AA, Graham MJ, Aberg PM, Axelsson BI. 60.  et al. 2000. Pharmacokinetic and toxicity profile of a phosphorothioate oligonucleotide following inhalation delivery to lung in mice. Antisense Nucleic Acid Drug Dev 10:359–68 [Google Scholar]
  61. Miner PB Jr., Wedel MK, Xia S, Baker BF, Geary RS, Matson J. 61.  2006. Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis. Aliment. Pharmacol. Ther. 23:1427–34 [Google Scholar]
  62. Tillman LG, Geary RS, Hardee GE. 62.  2008. Oral delivery of antisense oligonucleotides in man. J. Pharm. Sci. 97:225–36 [Google Scholar]
  63. Iversen PL. 63.  2008. Morpholinos. Antisense Drug Technology: Principles, Strategies, and Applications ST Crooke 565–82 Boca Raton, FL: CRC Press [Google Scholar]
  64. McMahon BM, Mays D, Lipsky J, Stewart JA, Fauq A, Richelson E. 64.  2002. Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration. Antisense Nucleic Acid Drug Dev. 12:65–73 [Google Scholar]
  65. Solano EC, Kornbrust DJ, Beaudry A, Foy JW, Schneider DJ, Thompson JD. 65.  2014. Toxicological and pharmacokinetic properties of QPI-1007, a chemically modified synthetic siRNA targeting caspase 2 mRNA, following intravitreal injection. Nucleic Acid Ther 24:258–66 [Google Scholar]
  66. Henry SP, Kim T-W, Kramer-Strickland K, Zanardi TA, Fey RA, Levin AA. 66.  2008. Toxicological properties of 2′-O-methoxyethyl chimeric antisense inhibitors in animals and man. Antisense Drug Technology: Principles, Strategies, and Applications ST Crooke 327–63 Boca Raton, FL: CRC Press [Google Scholar]
  67. Levin AA, Henry SP, Monteith D, Templin MV. 67.  2001. Toxicity of antisense oligonucleotides. Antisense Drug Technology: Principles, Strategies, and Applications ST Crooke 201–67 New York: Marcel Dekker, 1st ed.. [Google Scholar]
  68. Castanotto D, Rossi JJ. 68.  2009. The promises and pitfalls of RNA-interference-based therapeutics. Nature 457:426–33 [Google Scholar]
  69. Burel SA, Hart CE, Cauntay P, Hsiao J, Machemer T. 69.  et al. 2016. Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts. Nucleic Acids Res. 44:2093–109 [Google Scholar]
  70. Henry SP, Seguin R, Cavagnaro J, Berman C, Tepper J, Kornbrust D. 70.  2016. Considerations for the characterization and interpretation of results related to alternative complement activation in monkeys associated with oligonucleotide-based therapeutics. Nucleic Acid Ther 26:210–15 [Google Scholar]
  71. Jackson AL, Burchard J, Schelter J, Chau BN, Cleary M. 71.  et al. 2006. Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA 12:1179–87 [Google Scholar]
  72. Jackson AL, Linsley PS. 72.  2010. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat. Rev. Drug Discov. 9:57–67 [Google Scholar]
  73. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J. 73.  et al. 2003. Expression profiling reveals off-target gene regulation by RNAi. Nat. Biotechnol. 21:635–37 [Google Scholar]
  74. Sheehan JP, Phan TM. 74.  2001. Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex by an allosteric mechanism. Biochemistry 40:4980–89 [Google Scholar]
  75. Henry SP, Giclas PC, Leeds J, Pangburn M, Auletta C. 75.  et al. 1997. Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J. Pharmacol. Exp. Ther. 281:810–16 [Google Scholar]
  76. Monteith DK, Henry SP, Howard RB, Flournoy S, Levin AA. 76.  et al. 1997. Immune stimulation—a class effect of phosphorothioate oligodeoxynucleotides in rodents. Anticancer Drug Des 12:421–32 [Google Scholar]
  77. Senn JJ, Burel S, Henry SP. 77.  2005. Non-CpG-containing antisense 2′-methoxyethyl oligonucleotides activate a proinflammatory response independent of Toll-like receptor 9 or myeloid differentiation factor 88. J. Pharmacol. Exp. Ther. 314:972–79 [Google Scholar]
  78. Kwoh JT. 78.  2008. An overview of the clinical safety experience of first- and second-generation antisense oligonucleotides. Antisense Drug Technology: Principles, Strategies, and Applications ST Crooke 365–99 Boca Raton, FL: CRC Press [Google Scholar]
  79. Crooke ST, Baker BF, Kwoh TJ, Cheng W, Schulz DJ. 79.  et al. 2016. Integrated safety assessment of 2′-O-methoxyethyl chimeric antisense oligonucleotides in nonhuman primates and healthy human volunteers. Mol. Ther. 10:1771–82 [Google Scholar]
  80. Crooke ST. 80.  2008. Antisense Drug Technology: Principles, Strategies, and Applications Boca Raton, FL: CRC Press
  81. de Fougerolles AR, Maraganore JM. 81.  2007. Discovery and development of RNAi therapeutics. Antisense Drug Technology: Principles, Strategies, and Applications ST Crooke Boca Raton, FL: CRC Press [Google Scholar]
  82. Zhou Y, Zhang C, Liang W. 82.  2014. Development of RNAi technology for targeted therapy—a track of siRNA based agents to RNAi therapeutics. J. Control. Release 193:270–81 [Google Scholar]
  83. Piascik P. 83.  1999. Fomiversen sodium approved to treat CMV retinitis. J. Am. Pharm. Assoc. 39:84–85 [Google Scholar]
  84. Geary RS, Baker BF, Crooke ST. 84.  2015. Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (Kynamro): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B. Clin. Pharmacokinet. 54:133–46 [Google Scholar]
  85. Raal FJ, Braamskamp MJ, Selvey SL, Sensinger CH, Kastelein JJP. 85.  2016. Pediatric experience with mipomersen as adjunctive therapy for homozygous familial hypercholesterolemia. J. Clin. Lipidol. 10:860–69 [Google Scholar]
  86. Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen-Thiessen E, Tsimikas S. 86.  2015. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler. Thromb. Vasc. Biol. 35:689–99 [Google Scholar]
  87. Yu RZ, Gunawan R, Li Z, Mittleman RS, Mahmood A. 87.  et al. 2016. No effect on QT intervals of mipomersen, a 2′-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects. Eur. J. Clin. Pharmacol. 72:267–75 [Google Scholar]
  88. Graham MJ, Lee RG, Bell TA III, Fu W, Mullick AE. 88.  et al. 2013. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ. Res. 112:1479–90 [Google Scholar]
  89. Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J. 89.  et al. 2008. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322:1702–5 [Google Scholar]
  90. Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W. 90.  et al. 2014. Targeting APOC3 in the familial chylomicronemia syndrome. N. Engl. J. Med. 371:2200–6 [Google Scholar]
  91. Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K. 91.  et al. 2015. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373:438–47 [Google Scholar]
  92. Buller HR, Bethune C, Bhanot S, Gailani D, Monia BP. 92.  et al. 2015. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N. Engl. J. Med. 372:232–40 [Google Scholar]
  93. Monteleone G, Fantini MC, Onali S, Zorzi F, Sancesario G. 93.  et al. 2012. Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn's disease. Mol. Ther. 20:870–76 [Google Scholar]
  94. Monteleone G, Neurath MF, Ardizzone S, Di Sabatino A, Fantini MC. 94.  et al. 2015. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N. Engl. J. Med. 372:1104–13 [Google Scholar]
  95. Yacyshyn BR, Chey WY, Wedel MK, Yu RZ, Paul D, Cheung E. 95.  2007. A randomized, double-masked, placebo-controlled study of alicaforsen, an antisense inhibitor of intercellular adhesion molecule 1, for the treatment of subjects with active Crohn's disease. Clin. Gastroenterol. Hepatol. 5:215–20 [Google Scholar]
  96. Miner P, Wedel M, Bane B, Bradley J. 96.  2004. An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis. Aliment. Pharmacol. Ther. 19:281–86 [Google Scholar]
  97. Miner PB Jr., Wedel MK, Xia S, Baker BF. 97.  2006. Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: a randomized, double-blind, active-controlled trial. Aliment. Pharmacol. Ther. 23:1403–13 [Google Scholar]
  98. Van Deventer SJH, Wedel MK, Baker BF, Xia S, Chuang E, Miner PB Jr. 98.  2006. A Phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis. Aliment. Pharmacol. Ther. 23:1415–25 [Google Scholar]
  99. Greuter T, Biedermann L, Rogler G, Sauter B, Seibold F. 99.  2016. Alicaforsen, an antisense inhibitor of ICAM-1, as treatment for chronic refractory pouchitis after proctocolectomy: a case series. United Eur. Gastroenterol. J. 4:97–104 [Google Scholar]
  100. Bayever E, Iversen P, Smith S, Spinolo J, Zon G. 100.  1992. Systemic human antisense therapy begins. Antisense Res. Dev. 2:109–10 [Google Scholar]
  101. Zielinski R, Chi KN. 101.  2012. Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin in development for the treatment of prostate cancer. Future Oncol. 8:1239–51 [Google Scholar]
  102. Hong D, Kurzrock R, Kim Y, Woessner R, Younes A. 102.  et al. 2015. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci. Transl. Med. 7:314ra185 [Google Scholar]
  103. Yamamoto Y, Loriot Y, Beraldi E, Zhang F, Wyatt AW. 103.  et al. 2015. Generation 2.5 antisense oligonucleotides targeting the androgen receptor and its splice variants suppress enzalutamide-resistant prostate cancer cell growth. Clin. Cancer Res. 21:1675–87 [Google Scholar]
  104. Grondin R, Ge P, Chen Q, Sutherland JE, Zhang Z. 104.  et al. 2015. Onset time and durability of huntingtin suppression in rhesus putamen after direct infusion of antihuntingtin siRNA. Mol. Ther. Nucleic Acids 4:e245 [Google Scholar]
  105. McCormack AL, Mak SK, Henderson JM, Bumcrot D, Farrer MJ, Di Monte DA. 105.  2010. α-Synuclein suppression by targeted small interfering RNA in the primate substantia nigra. PLOS ONE 5:e12122 [Google Scholar]
  106. Flanigan KM. 106.  2014. Duchenne and Becker muscular dystrophies. Neurol. Clin. 32:671–88 [Google Scholar]
  107. Alter J, Lou F, Rabinowitz A, Yin HF, Rosenfeld J. 107.  et al. 2006. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat. Med. 12:175–77 [Google Scholar]
  108. Aartsma-Rus A, Janson AA, Kaman WE, Bremmer-Bout M, den Dunnen JT. 108.  et al. 2003. Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients. Hum. Mol. Genet. 12:907–14 [Google Scholar]
  109. Arechavala-Gomeza V, Graham IR, Popplewell LJ, Adams AM, Aartsma-Rus A. 109.  et al. 2007. Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Hum. Gene Ther. 18:798–810 [Google Scholar]
  110. Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF. 110.  et al. 2011. Systemic administration of PRO051 in Duchenne's muscular dystrophy. N. Engl. J. Med. 364:1513–22 [Google Scholar]
  111. Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L. 111.  et al. 2013. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann. Neurol. 74:637–47 [Google Scholar]
  112. Cirak S, Feng L, Anthony K, Arechavala-Gomeza V, Torelli S. 112.  et al. 2012. Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy. Mol. Ther. 20:462–67 [Google Scholar]
  113. Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K. 113.  et al. 2016. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann. Neurol. 79:257–71 [Google Scholar]
  114. Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D. 114.  et al. 1992. Molecular basis of myotnic dystrophy: expansion of a trinucleotides (CTG) repeat at the 3′-end of a transcript encoding a protein kinase family member. Cell 68:799–808 [Google Scholar]
  115. Mankodi A, Urbinati CR, Yuan QP, Moxley RT, Sansone V. 115.  et al. 2001. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum. Mol. Genet. 10:2165–70 [Google Scholar]
  116. Mulders SA, van den Broek WJ, Wheeler TM, Croes HJ, van Kuik-Romeijn P. 116.  et al. 2009. Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy. PNAS 106:13915–20 [Google Scholar]
  117. Wheeler TM, Sobczak K, Lueck JD, Osborn RJ, Lin X. 117.  et al. 2009. Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 325:336–39 [Google Scholar]
  118. Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M. 118.  et al. 2012. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 488:111–15 [Google Scholar]
  119. Pandey SK, Wheeler TM, Justice SL, Kim A, Younis HS. 119.  et al. 2015. Identification and characterization of modified antisense oligonucleotides targeting DMPK in mice and nonhuman primates for the treatment of myotonic dystrophy type 1. J. Pharmacol. Exp. Ther. 355:329–40 [Google Scholar]
  120. Gertz MA, Benson MD, Dyck PJ, Grogan M, Coelho T. 120.  et al. 2015. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J. Am. Coll. Cardiol. 66:2451–66 [Google Scholar]
  121. Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN. 121.  et al. 2013. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med. 369:819–29 [Google Scholar]
  122. Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I. 122.  et al. 2015. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J. Rare Dis. 10:109 [Google Scholar]
  123. Benson MD, Ackermann EJ, Monia BP. 123.  2015. Treatment of transthyretin (TTR) amyloid cardiomyopathy with an antisense oligonucleotide inhibitor of TTR synthesis. Orphanet J. Rare Dis. 10:7 [Google Scholar]
  124. Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O. 124.  et al. 1997. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat. Genet. 16:265–69 [Google Scholar]
  125. Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP. 125.  et al. 2011. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci. Transl. Med. 3:72ra18 [Google Scholar]
  126. Hua Y, Sahashi K, Hung G, Rigo F, Passini MA. 126.  et al. 2010. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 24:1634–44 [Google Scholar]
  127. Haché M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A. 127.  et al. 2016. Intrathecal injections in children with spinal muscular atrophy: nusinersen clinical trial experience. J. Child Neurol. 31:899–906 [Google Scholar]
  128. Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J. 128.  et al. 2016. Nusinersen treatment of infantile-onset spinal muscular atrophy. Lancet. In press
  129. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. 129.  2005. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309:1577–81 [Google Scholar]
  130. van der Meer AJ, Farid WR, Sonneveld MJ, de Ruiter PE, Boonstra A. 130.  et al. 2013. Sensitive detection of hepatocellular injury in chronic hepatitis C patients with circulating hepatocyte-derived microRNA-122. J. Viral Hepat. 20:158–66 [Google Scholar]
  131. Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M. 131.  et al. 2010. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327:198–201 [Google Scholar]
  132. Janssen HLA, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M. 132.  et al. 2013. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 368:1685–94 [Google Scholar]
  133. van der Ree MH, van der Meer AJ, de Bruijne J, Maan R, van Vliet A. 133.  et al. 2014. Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients. Antiviral Res 111:53–59 [Google Scholar]
  134. van der Meer AJ, de Vree ML, Stelma F, Willemse S, van der Valk M. 134.  et al. 2015. LO7: a single subcutaneous dose of 2 mg/kg or 4 mg/kg of RG-101, a GalNAc-conjugated oligonucleotide with antagonist activity against miR-122, results in significant viral load reductions in chronic hepatitis C patients. J. Hepatol. 62:S261 [Google Scholar]
  135. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ. 135.  et al. 2015. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386:1472–83 [Google Scholar]
  136. van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A. 136.  et al. 2007. Local dystrophin restoration with antisense oligonucleotide PRO051. N. Engl. J. Med. 357:2677–86 [Google Scholar]
  137. Saad F, Hotte S, North S, Eigl B, Chi K. 137.  et al. 2011. Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate-resistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c. Clin. Cancer Res. 17:5765–73 [Google Scholar]
  138. Chi KN, Siu LL, Hirte H, Hotte SJ, Knox J. 138.  et al. 2008. A phase I study of OGX-011, a 2′-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer. Clin. Cancer Res. 14:833–39 [Google Scholar]
  139. Chi KN, Yu EY, Jacobs C, Bazov J, Kollmannsberger C. 139.  et al. 2016. A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers. Ann. Oncol. 27:1116–22 [Google Scholar]
  140. Limmroth V, Barkhof F, Desem N, Diamond MP, Tachas G. 140.  ATL1102 Study Group 2014. CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS. Neurology 83:1780–88 [Google Scholar]
  141. Krug N, Hohlfeld JM, Kirsten AM, Kornmann O, Beeh KM. 141.  et al. 2015. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N. Engl. J. Med. 372:1987–95 [Google Scholar]
  142. Gish RG, Yuen MF, Chan HL, Given BD, Lai CL. 142.  et al. 2015. Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent. Antivir. Res. 121:97–108 [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010716-104846
Loading
/content/journals/10.1146/annurev-pharmtox-010716-104846
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error