Safety of antisense oligonucleotide and siRNA-based therapeutics

Drug Discovery Today

Volumn 22, Issue 5, 2017, Pages 823-833

  Chi, Xuan ^a   Gatti, Philip ^a   Papoian, Thomas ^a  

^a CENTER FOR DRUG EVALUATION AND RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; PREALBUMIN; REVUSIRAN; SMALL INTERFERING RNA;

3' UNTRANSLATED REGION; ATTR AMYLOIDOSIS; CHEMICAL MODIFICATION; CONFORMATIONAL TRANSITION; CONSERVED SEQUENCE; DRUG MECHANISM; DRUG SAFETY; GENE SILENCING; GENE TARGETING; HUMAN; LIVER CELL; LIVER TOXICITY; NONHUMAN; PERIPHERAL NEUROPATHY; PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; THROMBOCYTOPENIA; ANIMAL; CHEMISTRY;

ANIMALS; HUMANS; OLIGONUCLEOTIDES, ANTISENSE; RNA, SMALL INTERFERING;

EID: 85013124581     PISSN: 13596446     EISSN: 18785832     Source Type: Journal    
DOI: 10.1016/j.drudis.2017.01.013     Document Type: Review

References (77)

1. 1 Juliano, R.L., Ming, X., Recent developments in oligonucleotide based therapeutics. Preface. Adv. Drug Deliv. Rev. 87 (2015), 1–2.
2. 2 Bertrand, J.R., et al. Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo. Biochem. Biophys. Res. Commun. 296 (2002), 1000–1004.
3. 3 Miyagishi, M., et al. Comparison of the suppressive effects of antisense oligonucleotides and siRNAs directed against the same targets in mammalian cells. Antisense Nucleic Acid Drug Dev. 13 (2003), 1–7.
4. 4 Grunweller, A., et al. Comparison of different antisense strategies in mammalian cells using locked nucleic acids, 2'-O-methyl RNA, phosphorothioates and small interfering RNA. Nucleic Acids Res. 31 (2003), 3185–3193.
5. 5 Kretschmer-Kazemi Far, R., Sczakiel, G., The activity of siRNA in mammalian cells is related to structural target accessibility: a comparison with antisense oligonucleotides. Nucleic Acids Res. 31 (2003), 4417–4424.
6. 6 Vickers, T.A., et al. Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J. Biol. Chem. 278 (2003), 7108–7118.
7. 7 Crooke, S.T., et al. Integrated safety assessment of 2′-O-methoxyethyl chimeric antisense oligonucleotides in nonhuman primates and healthy human volunteers. Mol. Ther. 24 (2016), 1771–1782.
8. 8 Ionis Antisense Platform Safety Questioned After Thrombocytopenia Seen In Studies. 2016, Pink Sheet Daily.
9. 9 Watts, J.K., Corey, D.R., Silencing disease genes in the laboratory and the clinic. J. Pathol. 226 (2012), 365–379.
10. 10 Wittrup, A., Lieberman, J., Knocking down disease: a progress report on siRNA therapeutics. Nat. Rev. Genet. 16 (2015), 543–552.
11. 11 Fire, A., Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391 (1998), 806–811.
12. 12 Tuschl, T., RNA interference and small interfering RNAs. ChemBioChem 2 (2001), 239–245.
13. 13 Flierl, U., Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators. J. Exp. Med. 212 (2015), 129–137.
14. 14 Farman, C.A., Kornbrust, D.J., Oligodeoxynucleotide studies in primates: antisense and immune stimulatory indications. Toxicol. Pathol. 31:Suppl (2003), 119–122.
15. 15 Mansoor, M., Melendez, A.J., Advances in antisense oligonucleotide development for target identification, validation, and as novel therapeutics. Gene Regul. Syst. Biol. 2 (2008), 275–295.
16. 16 Henry, S.P., et al. Complement activation is responsible for acute toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide. Int. Immunopharmacol. 2 (2002), 1657–1666.
17. 17 Engelhardt, J.A., et al. Scientific and Regulatory Policy Committee points-to-consider paper: drug-induced vascular injury associated with nonsmall molecule therapeutics in preclinical development: part 2. Antisense oligonucleotides. Toxicol. Pathol. 43 (2015), 935–944.
18. 18 Shen, L., et al. Mechanistic understanding for the greater sensitivity of monkeys to antisense oligonucleotide-mediated complement activation compared with humans. J. Pharmacol. Exp. Ther. 351 (2014), 709–717.
19. 19 Frazier, K.S., Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist's perspective. Toxicol. Pathol. 43 (2015), 78–89.
20. 20 Frazier, K.S., et al. Species-specific inflammatory responses as a primary component for the development of glomerular lesions in mice and monkeys following chronic administration of a second-generation antisense oligonucleotide. Toxicol. Pathol. 42 (2014), 923–935.
21. 21 Judge, A.D., et al. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol. Ther. 13 (2006), 494–505.
22. 22 Wu, S.Y., et al. 2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nat. Commun., 5, 2014, 3459.
23. 23 Kenski, D.M., et al. siRNA-Optimized modifications for enhanced in vivo activity. Mol. Ther. Nucleic Acids, 1, 2012, e5.
24. 24 Prakash, T.P., et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 42 (2014), 8796–8807.
25. 25 Yu, R.Z., et al. Disposition and pharmacology of a GalNAc3-conjugated ASO targeting human lipoprotein (a) in mice. Mol. Ther. Nucleic Acids, 5, 2016, e317.
26. 26 Matsuda, S., et al. siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chem. Biol 10 (2015), 1181–1187.
27. 27 Alnylam Pharmaceuticals, RNAi therapeutics using conjugate delivery platform. 2013 Available at: http://www.alnylam.com/web/wp-content/uploads/2013/10/ALNY-ConjugateUpdate-OTS2013.pdf.
28. 28 Henry, S.P., et al. Toxicologic properties of 2′-O-methoxyethyl chimeric antisense inhibitors in animals and man. Crooke, S.T., (eds.) Antisense Drug Technology: Principles, Strategies and Applications, 2007, CRC, 327–364.
29. 29 Levin, A.A., Henry, S.P., Toxicology of oligonucleotide therapeutics and understanding the relevance of the toxicities. Pharmaceutical Sciences Encyclopedia 24 (2008), 1–38.
30. 30 Henry, S.P., Drug properties of second-generation antisense oligonucleotides: how do they measure up to their predecessors?. Curr. Opin. Investig. Drugs 2 (2001), 1444–1449.
31. 31 Sewell, K.L., et al. Phase I trial of ISIS 104838, a 2'-methoxyethyl modified antisense oligonucleotide targeting tumor necrosis factor-alpha. J. Pharmacol. Exp. Ther. 303 (2002), 1334–1343.
32. 32 Hong, D.S., et al. A Phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer. Clin. Cancer Res. 17 (2011), 6582–6591.
33. 33 Coudert, B., et al. Phase II trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLC) lung cancer: A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report. Eur. J. Cancer 37 (2001), 2194–2198.
34. 34 (2013) KYNAMRO –mipomersen sodium injection, solution. Official Label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203568s008lbl.pdf.
35. 35 Limmroth, V., et al. CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS. Neurology 83 (2014), 1780–1788.
36. 36 Powers, M., Ionis sinks as company, investors fret over meaning of platelet signal. BioWorld, 2016.
37. 37 (2015) PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS ADVISORY COMMITTEE-DRISAPERSEN BRIEFING DOCUMENT. In NDA 206031: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM473737.pdf.
38. 38 Tefferi, A., et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N. Engl. J. Med. 373 (2015), 908–919.
39. 39 Salloum, R., et al. A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study. J. Neurooncol. 129 (2016), 443–451.
40. 40 Tefferi, A., Telomerase inhibitor imetelstat in essential thrombocythemia and myelofibrosis. N. Engl. J. Med. 373 (2015), 2580–2581.
41. 41 Gene and Cell Therapy: Therapeutic Mechanisms and Strategies. Templeton, N.S., (eds.), 4th edn, 2015, CRC Press.
42. 42 Kwoh, T.J., An overview of the clinical safety experience of first-and second-generation antisense oligonucleotides. Crooke, S.T., (eds.) Antisense Drug Technology: Principles, Strategies and Applications, 2007, CRC, 365–399.
43. 43 Advisory Committee Meeting, FDA Briefing Document NDA 203568 – Endocrinologic and Metabolic Drugs. 2012.
44. 44 Tao, W., et al. Mechanistically probing lipid-siRNA nanoparticle-associated toxicities identifies Jak inhibitors effective in mitigating multifaceted toxic responses. Mol. Ther. 19 (2011), 567–575.
45. 45 Xue, H.Y., et al. Lipid-based nanocarriers for RNA delivery. Curr. Pharm. Des. 21 (2015), 3140–3147.
46. 46 Lorenzer, C., et al. Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics. J. Control. Release 203 (2015), 1–15.
47. 47 Ozcan, G., et al. Preclinical and clinical development of siRNA-based therapeutics. Adv. Drug Deliv. Rev. 87 (2015), 108–119.
48. 48 Szebeni, J., et al. Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv. Drug Deliv. Rev. 63 (2011), 1020–1030.
49. 49 Mahoharan, M., TIDES 2014 GalNAc-siRNA with enhanced stabilization chemistry: ESC-GalNAc-siRNA. 2014 Available at: http://www.alnylam.com/web/assets/ALNY-ESC-GalNAc-siRNA-TIDES-May2014-Capella.pdf.
50. 50 Obici, L., Merlini, G., An overview of drugs currently under investigation for the treatment of transthyretin-related hereditary amyloidosis. Expert Opin. Investig. Drugs 23 (2014), 1239–1251.
51. 51 Sekijima, Y., Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J. Neurol. Neurosurg. Psychiatry 86 (2015), 1036–1043.
52. 52 Ackermann, E.J., et al. Suppressing transthyretin production in mice, monkeys and humans using 2nd-generation antisense oligonucleotides. Amyloid, 2016, 10.1080/13506129.2016.1191458.
53. 53 Ackermann, E.J., et al. Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. Amyloid 19:Suppl. 1 (2012), 43–44.
54. 54 Niemietz, C., et al. Therapeutic oligonucleotides targeting liver disease: TTR amyloidosis. Molecules 20 (2015), 17944–17975.
55. 55 Yu, R.Z., Predictive dose-based estimation of systemic exposure multiples in mouse and monkey relative to human for antisense oligonucleotides with 2'-o-(2-methoxyethyl) modifications. Mol. Ther. Nucleic Acids, 4, 2015, e218.
56. 56 Butler, J.S., et al. Preclinical evaluation of RNAi as a treatment for transthyretin-mediated amyloidosis. Amyloid 23 (2016), 109–118.
57. 57 Ledford, H., Investors flee as firm scraps RNA-interference drug candidate. Nature, 2016, 10.1038/nature.2016.20769.
58. 58 Fidler, B., Alnylam scraps RNAi drug after safety problems, shares plunge. 2016 Available at: http://www.xconomy.com/boston/2016/10/05/alnylam-scraps-rnai-drug-after-safety-problems-shares-plunge/.
59. 59 Isis Pharmaceuticals Reports Positive Data From ISIS-TTR Rx in Patients With TTR Amyloidosis. Available at: http://www.prnewswire.com/news-releases/isis-pharmaceuticals-reports-positive-data-from-isis-ttr-rx-in-patients-with-ttr-amyloidosis-300070552.html.
60. 60 Prakash, T.P., et al. Comprehensive structure-activity relationship of triantennary N-acetylgalactosamine conjugated antisense oligonucleotides for targeted delivery to hepatocytes. J. Med. Chem. 59 (2016), 2718–2733.
61. 61 Alnylam Pharmaceuticals Discontinues Revusiran Development. Available at: http://investors.alnylam.com/releasedetail.cfm?ReleaseID=992320.
62. 62 Heart Failure Society of America Annual Scientific Meeting-ALN-TTRsc Phase I Study Results. Available at: http://www.alnylam.com/web/wp-content/uploads/2013/09/ALN-TTRsc-PhaseI-Results-HFSA-Sept2013.pdf.
63. 63 A Phase 2 Multi-Center, Open-Label Trial to Evaluate the Safety,Pharmacokinetics, Pharmacodynamics and Exploratory Clinical Activity of Revusiran (ALN-TTRsc), an RNAi Therapeutic for the Treatment of Patients with Transthyretin Cardiac Amyloidosis. Available at: http://www.alnylam.com/web/assets/Revusiran-ACC-15Mar2015.pdf.
64. 64 Updates from Patisiran and Revusiran, in Development for the Treatment of hATTR Amyloidosis. Available at: http://www.alnylam.com/capella/presentations/updates-from-patisiran-and-revusiran-for-hattr-amyloidosis/.
65. 65 Alnylam Reports Positive Results from Ongoing Phase 2 Open-Label Extension (OLE) Studies for Patisiran and Revusiran, in Development for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis (ATTR Amyloidosis). Available at: http://investors.alnylam.com/releasedetail.cfm?ReleaseID=939975.
66. 66 Coelho, T., et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med. 369 (2013), 819–829.
67. 67 In patients with TTR amyloidosis (ATTR) clinically manifesting as symptomatic polyneuropathy (FAP), ALN-TTR02, an RNAi therapeutic, demonstrated robust pharmacodynamic activity and was generally well tolerated in a Phase II study. Available at: http://www.alnylam.com/TTR02-Clinical/DataSheet-Nov2013.pdf.
68. 68 Suhr, O.B., et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a Phase II multi-dose study. Orphanet J. Rare Dis., 10, 2015, 109.
69. 69 Iannitti, T., et al. Phosphorothioate oligonucleotides: effectiveness and toxicity. Curr. Drug Targets 15 (2014), 663–673.
70. 70 Hebb, M.O., Robertson, H.A., End-capped antisense oligodeoxynucleotides effectively inhibit gene expression in vivo and offer a low-toxicity alternative to fully modified phosphorothioate oligodeoxynucleotides. Brain Res. Mol. Brain Res. 47 (1997), 223–228.
71. 71 Alnylam, Alnylam Announces Positive Initial Phase 2 Data with Revusiran (ALN-TTRsc), an Investigational RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of TTR Cardiac Amyloidosis, with up to 98.2% Knockdown of Serum TTR in Patients, 2014, Available at: http://investors.alnylam.com/releasedetail.cfm?ReleaseID=883025.
72. 72 Biogen, Biogen and Ionis Pharmaceuticals Report Nusinersen Meets Primary Endpoint at Interim Analysis of Phase 3 ENDEAR Study in Infantile-Onset Spinal Muscular Atrophy, 2016, Available at: http://media.biogen.com/press-release/investor-relations/biogen-and-ionis-pharmaceuticals-report-nusinersen-meets-primary-en.
73. 73 Heale, B.S., et al. siRNA target site secondary structure predictions using local stable substructures. Nucleic Acids Res., 33, 2005, e30.
74. 74 Sun, Y., et al. The influence of RNA secondary structure on efficiency of siRNA silencing. Long, M., (eds.) World Congress on Medical Physics and Biomedical Engineering, 2013, Springer, 398–401.
75. 75 Jaax, M.E., et al. Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4. Blood 122 (2013), 272–281.
76. 76 Hartmann, G., et al. Oligodeoxynucleotides enhance lipopolysaccharide-stimulated synthesis of tumor necrosis factor: dependence on phosphorothioate modification and reversal by heparin. Mol. Med. 2 (1996), 429–438.
77. 77 Morrell, C.N., Emerging roles for platelets as immune and inflammatory cells. Blood 123 (2014), 2759–2767.