Chemical Development of Therapeutic Oligonucleotides

  • Karin E. LundinEmail author
  • Olof Gissberg
  • C. I. Edvard Smith
  • Rula Zain
Part of the Methods in Molecular Biology book series (MIMB, volume 2036)


The development of several different chemical modifications of nucleic acids, with improved base-pairing affinity and specificity as well as increased resistance against nucleases, has been described. These new chemistries have allowed the synthesis of different types of therapeutic oligonucleotides. Here we discuss selected chemistries used in antisense oligonucleotide (ASO) applications (e.g., small interfering RNA (siRNA), RNase H activation, translational block, splice-switching, and also as aptamers). Recently approved oligonucleotide-based drugs are also presented briefly.

Key words

Base analogs Ribose modifications Phosphodiester linkage Phosphorodiamidate morpholino (PMO) Locked nucleic acid (LNA) Peptide nucleic acid (PNA) Tricyclo-DNA 



This work was supported by the Swedish Research Council, the Stockholm County Council, Hjärnfonden, and Vinnova/SweLife.


  1. 1.
    Reist EJ, Benitez A, Goodman L (1964) The synthesis of some 5′-thiopentofuranosylpyrimidines. J Org Chem 29(3):554–558CrossRefGoogle Scholar
  2. 2.
    Codington JF, Doerr IL, Fox JJ (1964) Nucleosides. XVIII. Synthesis of 2′-fluorothymidine, 2′-fluorodeoxyuridine, and other 2′-halogeno-2′-deoxy nucleosides. J Org Chem 29(3):558–564CrossRefGoogle Scholar
  3. 3.
    Eckstein F (1966) Nucleoside phosphorothioates. J Am Chem Soc 88:4292–4294CrossRefGoogle Scholar
  4. 4.
    Bobst AM, Rottman F, Cerutti PA (1969) Effect of the methylation of the 2′-hydroxyl groups in polyadenylic acid on its structure in weakly acidic and neutral solutions and on its capability to form ordered complexes with polyuridylic acid. J Mol Biol 46(2):221–234PubMedCrossRefGoogle Scholar
  5. 5.
    Martin P (1995) Ein neuer zugang zu 2′-O-alkylribonucleosiden und eigenschaften deren oligonucleotide. Helv Chim Acta 78(2):486–504CrossRefGoogle Scholar
  6. 6.
    Summerton J, Weller D (1997) Morpholino antisense oligomers: design, preparation, and properties. Antisense Nucleic Acid Drug Dev 7(3):187–195PubMedCrossRefGoogle Scholar
  7. 7.
    Nielsen PE, Egholm M, Berg RH, Buchardt O (1991) Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 254(5037):1497–1500PubMedCrossRefGoogle Scholar
  8. 8.
    Nielsen P, Dreioe LH, Wengel J (1995) Synthesis and evaluation of oligodeoxynucleotides containing acyclic nucleosides: introduction of three novel analogues and a summary. Bioorg Med Chem 3(1):19–28PubMedCrossRefGoogle Scholar
  9. 9.
    Obika S, Nanbu D, Hari Y, Morio K-I, In Y, Ishida T et al (1997) Synthesis of 2′-O, 4′-C-methyleneuridine and -cytidine. Novel bicyclic nucleosides having a fixed C3′-endo sugar puckering. Tetrahedron Lett 38:8735–8738CrossRefGoogle Scholar
  10. 10.
    Koshkin AA, Singh SK, Nielsen P, Rajwanshi VK, Kumar R, Meldgaard M et al (1998) Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition. Tetrahedron 54:3607–3630CrossRefGoogle Scholar
  11. 11.
    Seth PP, Siwkowski A, Allerson CR, Vasquez G, Lee S, Prakash TP et al (2009) Short antisense oligonucleotides with novel 2′-4′ conformationaly restricted nucleoside analogues show improved potency without increased toxicity in animals. J Med Chem 52(1):10–13PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Renneberg D, Leumann CJ (2002) Watson-crick base-pairing properties of tricyclo-DNA. J Am Chem Soc 124(21):5993–6002PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Lundin KE, Gissberg O, Smith CI (2015) Oligonucleotide therapies: the past and the present. Hum Gene Ther 26(8):475–485PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Smith CIE, Zain R (2019) Therapeutic oligonucleotides: state of the art. Annu Rev Pharmacol Toxicol 59:605–630CrossRefGoogle Scholar
  15. 15.
    Terrazas M, Kool ET (2009) RNA major groove modifications improve si RNA stability and biological activity. Nucleic Acids Res 37(2):346–353PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Ostergaard ME, Kumar P, Nichols J, Watt A, Sharma PK, Nielsen P et al (2015) Allele-selective inhibition of mutant huntingtin with 2-thio- and C5- triazolylphenyl-deoxythymidine-modified antisense oligonucleotides. Nucleic Acid Ther. 25(5):266–274PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Wan WB, Seth PP (2016) The medicinal chemistry of therapeutic oligonucleotides. J Med Chem 59(21):9645–9667PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Henry S, Stecker K, Brooks D, Monteith D, Conklin B, Bennett CF (2000) Chemically modified oligonucleotides exhibit decreased immune stimulation in mice. J Pharmacol Exp Ther 292(2):468–479PubMedPubMedCentralGoogle Scholar
  19. 19.
    Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC et al (2010) Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 375(9719):998–1006PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Gidaro T, Servais L (2019) Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps. Dev Med Child Neurol 61(1):19–24PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Lundin KE, Hojland T, Hansen BR, Persson R, Bramsen JB, Kjems J et al (2013) Biological activity and biotechnological aspects of locked nucleic acids. Adv Genet 82:47–107PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Lou C, Samuelsen SV, Christensen NJ, Vester B, Wengel J (2017) Oligonucleotides containing aminated 2′-amino-LNA nucleotides: synthesis and strong binding to complementary DNA and RNA. Bioconjug Chem 28(4):1214–1220PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Lee T, Awano H, Yagi M, Matsumoto M, Watanabe N, Goda R et al (2017) 2′-O-methyl RNA/ethylene-bridged nucleic acid chimera antisense oligonucleotides to induce dystrophin exon 45 skipping. Genes (Basel) 8(2)PubMedCentralCrossRefGoogle Scholar
  24. 24.
    Iribe H, Miyamoto K, Takahashi T, Kobayashi Y, Leo J, Aida M et al (2017) Chemical modification of the si RNA seed region suppresses off-target effects by steric hindrance to base-pairing with targets. ACS Omega 2(5):2055–2064PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Mook O, Vreijling J, Wengel SL, Wengel J, Zhou C, Chattopadhyaya J et al (2010) In vivo efficacy and off-target effects of locked nucleic acid (LNA) and unlocked nucleic acid (UNA) modified si RNA and small internally segmented interfering RNA (sisi RNA) in mice bearing human tumor xenografts. Artif DNA PNA XNA 1(1):36–44PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kotkowiak W, Lisowiec-Wachnicka J, Grynda J, Kierzek R, Wengel J, Pasternak A (2018) Thermodynamic, anticoagulant, and Antiproliferative properties of thrombin binding aptamer containing novel UNA derivative. Mol Ther Nucleic Acids. 10:304–316PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Ferino A, Miglietta G, Picco R, Vogel S, Wengel J, Xodo LE (2018) Micro RNA therapeutics: design of single-stranded mi R-216b mimics to target KRAS in pancreatic cancer cells. RNA Biol 15(10):1273–1285PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Heidenreich O, Gryaznov S, Nerenberg M (1997) RNase H-independent antisense activity of oligonucleotide N3′--> P 5′ phosphoramidates. Nucleic Acids Res 25(4):776–780PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Schrank Z, Khan N, Osude C, Singh S, Miller RJ, Merrick C et al (2018) Oligonucleotides targeting telomeres and telomerase in cancer. Molecules 23(9)PubMedCentralCrossRefGoogle Scholar
  30. 30.
    Eckstein F (2014) Phosphorothioates, essential components of therapeutic oligonucleotides. Nucleic Acids Ther 24(6):374–387CrossRefGoogle Scholar
  31. 31.
    Iannitti T, Morales-Medina JC, Palmieri B (2014) Phosphorothioate oligonucleotides: effectiveness and toxicity. Curr Drug Targets 15(7):663–673PubMedCrossRefGoogle Scholar
  32. 32.
    Henry SP, Seguin R, Cavagnaro J, Berman C, Tepper J, Kornbrust D (2016) Considerations for the characterization and interpretation of results related to alternative complement activation in monkeys associated with oligonucleotide-based therapeutics. Nucleic Acids Ther 26(4):210–215CrossRefGoogle Scholar
  33. 33.
    Narayanan P, Shen L, Curtis BR, Bourdon MA, Nolan JP, Gupta S et al (2018) Investigation into the mechanism (s) that leads to platelet decreases in cynomolgus monkeys during administration of ISIS 104838, a 2′-MOE-modified antisense oligonucleotide. Toxicol Sci 164(2):613–626PubMedCrossRefGoogle Scholar
  34. 34.
    Crooke ST, Baker BF, Witztum JL, Kwoh TJ, Pham NC, Salgado N et al (2017) The effects of 2′-O-methoxyethyl containing antisense oligonucleotides on platelets in human clinical trials. Nucleic Acids Ther 27(3):121–129CrossRefGoogle Scholar
  35. 35.
    Stirchak EP, Summerton JE, Weller DD (1989) Uncharged stereoregular nucleic acid analogs: 2. Morpholino nucleoside oligomers with carbamate internucleoside linkages. Nucleic Acids Res 17(15):6129–6141PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Yokota T, Duddy W, Partridge T (2007) Optimizing exon skipping therapies for DMD. Acta Myol 26(3):179–184PubMedPubMedCentralGoogle Scholar
  37. 37.
    Du L, Gatti RA (2011) Potential therapeutic applications of antisense morpholino oligonucleotides in modulation of splicing in primary immunodeficiency diseases. J Immunol Methods 365(1–2):1–7PubMedCrossRefGoogle Scholar
  38. 38.
    Deas TS, Binduga-Gajewska I, Tilgner M, Ren P, Stein DA, Moulton HM et al (2005) Inhibition of flavivirus infections by antisense oligomers specifically suppressing viral translation and RNA replication. J Virol 79(8):4599–4609PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Nan Y, Zhang YJ (2018) Antisense Phosphorodiamidate Morpholino oligomers as novel antiviral compounds. Front Microbiol 9:750PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Lim KR, Maruyama R, Yokota T (2017) Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther 11:533–545PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Bestas B, Moreno PM, Blomberg KE, Mohammad DK, Saleh AF, Sutlu T et al (2014) Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model. J Clin Invest 124(9):4067–4081PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hammond SM, Hazell G, Shabanpoor F, Saleh AF, Bowerman M, Sleigh JN et al (2016) Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc Natl Acad Sci U S A 113(39):10962–10967PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Lundin KE, Good L, Stromberg R, Graslund A, Smith CI (2006) Biological activity and biotechnological aspects of peptide nucleic acid. Adv Genet 56:1–51PubMedCrossRefGoogle Scholar
  44. 44.
    Gupta A, Mishra A, Puri N (2017) Peptide nucleic acids: advanced tools for biomedical applications. J Biotechnol 259:148–159PubMedCrossRefGoogle Scholar
  45. 45.
    Narenji H, Gholizadeh P, Aghazadeh M, Rezaee MA, Asgharzadeh M, Kafil HS (2017) Peptide nucleic acids (PNAs): currently potential bactericidal agents. Biomed Pharmacother 93:580–588PubMedCrossRefGoogle Scholar
  46. 46.
    Babar IA, Cheng CJ, Booth CJ, Liang X, Weidhaas JB, Saltzman WM et al (2012) Nanoparticle-based therapy in an in vivo micro RNA-155 (mi R-155)-dependent mouse model of lymphoma. Proc Natl Acad Sci U S A 109(26):E1695–E1704PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Brognara E, Fabbri E, Aimi F, Manicardi A, Bianchi N, Finotti A et al (2012) Peptide nucleic acids targeting mi R-221 modulate p27Kip1 expression in breast cancer MDA-MB-231 cells. Int J Oncol 41(6):2119–2127PubMedCrossRefGoogle Scholar
  48. 48.
    Montazersaheb S, Hejazi MS, Nozad CH (2018) Potential of peptide nucleic acids in future therapeutic applications. Adv Pharm Bull 8(4):551–563PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Murray S, Ittig D, Koller E, Berdeja A, Chappell A, Prakash TP et al (2012) Tricyclo DNA-modified oligo-2′-deoxyribonucleotides reduce scavenger receptor B1 mRNA in hepatic and extra-hepatic tissues--a comparative study of oligonucleotide length, design and chemistry. Nucleic Acids Res 40(13):6135–6143PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Relizani K, Goyenvalle A (2018) Use of Tricyclo-DNA antisense oligonucleotides for exon skipping. Methods Mol Biol 1828:381–394PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Ivanova G, Reigadas S, Ittig D, Arzumanov A, Andreola ML, Leumann C et al (2007) Tricyclo-DNA containing oligonucleotides as steric block inhibitors of human immunodeficiency virus type 1 tat-dependent trans-activation and HIV-1 infectivity. Oligonucleotides 17(1):54–65PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Robin V, Griffith G, Carter JL, Leumann CJ, Garcia L, Goyenvalle A (2017) Efficient SMN rescue following subcutaneous Tricyclo-DNA antisense oligonucleotide treatment. Mol Ther Nucleic Acids 7:81–89PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Aupy P, Echevarria L, Relizani K, Goyenvalle A (2017) The use of Tricyclo-DNA oligomers for the treatment of genetic disorders. Biomedicine 6(1)PubMedCentralCrossRefGoogle Scholar
  54. 54.
    Geary RS, Henry SP, Grillone LR (2002) Fomivirsen: clinical pharmacology and potential drug interactions. Clin Pharmacokinet 41(4):255–260PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Anderson KP, Fox MC, Brown-Driver V, Martin MJ, Azad RF (1996) Inhibition of human cytomegalovirus immediate-early gene expression by an antisense oligonucleotide complementary to immediate-early RNA. Antimicrob Agents Chemother 40(9):2004–2011PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Ng EW, Shima DT, Calias P, Cunningham ET Jr, Guyer DR, Adamis AP (2006) Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 5(2):123–132PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Geary RS, Baker BF, Crooke ST (2015) Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro((R))): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B. Clin Pharmacokinet 54(2):133–146PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Yu RZ, Grundy JS, Henry SP, Kim TW, Norris DA, Burkey J et al (2015) 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:e218PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Sazani P, Ness KP, Weller DL, Poage DW, Palyada K, Shrewsbury SB (2011) Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of duchenne muscular dystrophy. Int J Toxicol 30(3):313–321PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF et al (2010) Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 24(15):1634–1644PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Yang J (2019) Patisiran for the treatment of hereditary transthyretin-mediated amyloidosis. Expert Rev Clin Pharmacol 12(2):95–99PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Shen X, Corey DR (2018) Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res 46(4):1584–1600PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Rodrigues M, Yokota T (2018) An overview of recent advances and clinical applications of exon skipping and splice modulation for muscular dystrophy and various genetic diseases. Methods Mol Biol 1828:31–55PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Khvorova A (2017) Oligonucleotide therapeutics – a new class of cholesterol-lowering drugs. N Engl J Med 376(1):4–7PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Zimmermann TS, Karsten V, Chan A, Chiesa J, Boyce M, Bettencourt BR et al (2017) Clinical proof of concept for a novel hepatocyte-targeting gal NAc-si RNA conjugate. Mol Ther 25(1):71–78PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Jackson SR, Zhu CH, Paulson V, Watkins L, Dikmen ZG, Gryaznov SM et al (2007) Antiadhesive effects of GRN163L – an oligonucleotide N3′->P 5′ thio-phosphoramidate targeting telomerase. Cancer Res 67(3):1121–1129PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Hamel Y, Lacoste J, Frayssinet C, Sarasin A, Garestier T, Francois JC et al (1999) Inhibition of gene expression by anti-sense C-5 propyne oligonucleotides detected by a reporter enzyme. Biochem J 339(Pt 3):547–553PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Wagner RW, Matteucci MD, Grant D, Huang T, Froehler BC (1996) Potent and selective inhibition of gene expression by an antisense heptanucleotide. Nat Biotechnol 14(7):840–844PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Kamiya Y, Donoshita Y, Kamimoto H, Murayama K, Ariyoshi J, Asanuma H (2017) Introduction of 2,6-diaminopurines into Serinol nucleic acid improves anti-mi RNA performance. Chembiochem 18(19):1917–1922PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Monia BP, Lesnik EA, Gonzalez C, Lima WF, McGee D, Guinosso CJ et al (1993) Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem 268(19):14514–14522PubMedGoogle Scholar
  71. 71.
    Goemans N, Mercuri E, Belousova E, Komaki H, Dubrovsky A, McDonald CM et al (2018) A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy. Neuromuscul Disord 28(1):4–15PubMedCrossRefGoogle Scholar
  72. 72.
    Maruyama R, Touznik A, Yokota T (2018) Evaluation of exon inclusion induced by splice switching antisense oligonucleotides in SMA patient fibroblasts. J Vis Exp 135Google Scholar
  73. 73.
    Lima JF, Carvalho J, Pinto-Ribeiro I, Almeida C, Wengel J, Cerqueira L et al (2018) Targeting mi R-9 in gastric cancer cells using locked nucleic acid oligonucleotides. BMC Mol Biol 19(1):6PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M et al (2005) Silencing of micro RNAs in vivo with ‘antagomirs’. Nature 438(7068):685–689PubMedCrossRefGoogle Scholar
  75. 75.
    Nulf CJ, Corey D (2004) Intracellular inhibition of hepatitis C virus (HCV) internal ribosomal entry site (IRES)-dependent translation by peptide nucleic acids (PNAs) and locked nucleic acids (LNAs). Nucleic Acids Res 32(13):3792–3798PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Edwards SL, Poongavanam V, Kanwar JR, Roy K, Hillman KM, Prasad N et al (2015) Targeting VEGF with LNA-stabilized G-rich oligonucleotide for efficient breast cancer inhibition. Chem Commun (Camb) 51(46):9499–9502CrossRefGoogle Scholar
  77. 77.
    Elle IC, Karlsen KK, Terp MG, Larsen N, Nielsen R, Derbyshire N et al (2015) Selection of LNA-containing DNA aptamers against recombinant human CD73. Mol BioSyst 11(5):1260–1270PubMedCrossRefGoogle Scholar
  78. 78.
    Volk DE, Lokesh GLR (2017) Development of phosphorothioate DNA and DNA thioaptamers. Biomedicine 5(3)Google Scholar
  79. 79.
    Faria M, Spiller DG, Dubertret C, Nelson JS, White MR, Scherman D et al (2001) Phosphoramidate oligonucleotides as potent antisense molecules in cells and in vivo. Nat Biotechnol 19(1):40–44PubMedCrossRefGoogle Scholar
  80. 80.
    Gryaznov SM (2010) Oligonucleotide n3′-->p 5′ phosphoramidates and thio-phoshoramidates as potential therapeutic agents. Chem Biodivers 7(3):477–493PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Gao X, Shen X, Dong X, Ran N, Han G, Cao L et al (2015) Peptide nucleic acid promotes systemic dystrophin expression and functional rescue in dystrophin-deficient mdx mice. Mol Ther Nucleic Acids 4:e255PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Siwkowski AM, Malik L, Esau CC, Maier MA, Wancewicz EV, Albertshofer K et al (2004) Identification and functional validation of PNAs that inhibit murine CD40 expression by redirection of splicing. Nucleic Acids Res 32(9):2695–2706PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Doyle DF, Braasch DA, Simmons CG, Janowski BA, Corey DR (2001) Inhibition of gene expression inside cells by peptide nucleic acids: effect of mRNA target sequence, mismatched bases, and PNA length. Biochemistry 40(1):53–64PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Karin E. Lundin
    • 1
    Email author
  • Olof Gissberg
    • 1
  • C. I. Edvard Smith
    • 2
  • Rula Zain
    • 1
    • 3
  1. 1.Department of Laboratory Medicine, Center for Advanced TherapiesKarolinska InstitutetStockholmSweden
  2. 2.Department of Laboratory Medicine, Center for Advanced Therapies, Karolinska University Hospital HuddingeKarolinska InstitutetStockholmSweden
  3. 3.Department of Clinical Genetics, Center for Rare DiseasesKarolinska University HospitalStockholmSweden

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