Skip to main content
SpringerLink
Log in
Book cover

Safety and Efficacy of Gene-Based Therapeutics for Inherited Disorders pp 191–217Cite as

Oligonucleotide Therapy

  • Chapter
  • First Online:

  • 979 Accesses

Abstract

Oligonucleotides (ONs), the focus of the chapter herein, are mostly known for their utility to selectively manipulate RNA processing by increasing or decreasing target gene levels, in particular by inducing enzymatic RNA degradation, blocking or mimicking miRNAs, inhibiting mRNA translation or modulating pre-mRNA splicing. Since these mechanisms of action are based on the Watson–Crick base pairing to target sequences, ONs are highly specific compounds. The possibility of a large scale and standardized production of these compounds makes them attractive for the therapy of inherited disorders. To date, four ONs have received marketing authorization and more than 100 have been, or are, under clinical trials. Several different oligonucleotide chemistries have been explored, each with its own delivery hurdles and toxicology patterns. Only a limited knowledge is available concerning the cellular and subcellular mechanisms of ONs uptake, transport and metabolism, presently making the improvement of ONs’ delivery and toxicology a challenging task. The purpose of this chapter is to review the state-of-the-art advances on ONs for applications in inherited disorders and give an overview of what is known regarding their delivery and safety, based on preclinical and clinical studies.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010;50:259–93.

    Article  CAS  PubMed  Google Scholar 

  2. Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, Lachmann RH, Gaudet D, Tan JL, Chasan-Taber S, Tribble DL, Flaim JD, Crooke ST. ‘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. 2010;375(9719):998–1006.

    Article  CAS  PubMed  Google Scholar 

  3. Vitravene Study Group. A randomized controlled clinical trial of intravitreous fomivirsen for treatment of newly diagnosed peripheral cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol. 2002;133:467–74.

    Article  Google Scholar 

  4. Vitravene Study Group. Randomized dose-comparison studies of intravitreous fomivirsen for treatment of cytomegalovirus retinitis that has reactivated or is persistently active despite other therapies in patients with AIDS. Am J Ophthalmol. 2002;133:475–83.

    Article  Google Scholar 

  5. Vitravene Study Group. Safety of intravitreous fomivirsen for treatment of cytomegalovirus retinitis in patients with AIDS. Am J Ophthalmol. 2002;133:484–98.

    Article  Google Scholar 

  6. Chiang MY, Chan H, Zounes MA, Freier SM, Lima WF, Bennett CF. Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. J Biol Chem. 1991;266(27):18162–71.

    CAS  PubMed  Google Scholar 

  7. Wu H, Lima WF, Zhang H, Fan A, Sun H, Crooke ST. Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs. J Biol Chem. 2004;279:17181–9.

    Article  CAS  PubMed  Google Scholar 

  8. Monia BP, Lesnik EA, Gonzalez C, Lima WF, McGee D, Guinosso CJ, Kawasaki AM, Cook PD, Freier SM. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem. 1993;268:14514–22.

    CAS  PubMed  Google Scholar 

  9. Chauhan NB, Siegel GJ. Antisense inhibition at the beta-secretase-site of beta-amyloid precursor protein reduces cerebral amyloid and acetyl cholinesterase activity in Tg2576. Neuroscience. 2007;146(1):143–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Østergaard ME, Southwell AL, Kordasiewicz H, Watt AT, Skotte NH, Doty CN, Vaid K, Villanueva EB, Swayze EE, Bennett CF, Hayden MR, Seth PP. Rational design of antisense oligonucleotides targeting single nucleotide polymorphisms for potent and allele selective suppression of mutant Huntingtin in the CNS. Nucleic Acids Res. 2013;41(21):9634–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Baker BF, Lot SS, Condon TP, Cheng-Flournoy S, Lesnik EA, Sasmor HM, Bennett CF. 2′-O-(2-Methoxy)ethyl-modified anti-intercellular adhesion molecule 1 (ICAM-1) oligonucleotides selectively increase the ICAM-1 mRNA level and inhibit formation of the ICAM-1 translation initiation complex in human umbilical vein endothelial cells. J Biol Chem. 1997;272(18):11994–2000.

    Article  CAS  PubMed  Google Scholar 

  12. Dias N, Dheur S, Nielsen PE, Gryaznov S, Van Aerschot A, Herdewijn P, Helene C, Saison-Behmoaras TE. Antisense PNA tridecamers targeted to the coding region of Ha-ras mRNA arrest polypeptide chain elongation. J Mol Biol. 1999;294:403–16.

    Article  CAS  PubMed  Google Scholar 

  13. Hélène C, Toulmé JJ. Specific regulation of gene expression by antisense, sense and antigene nucleic acids’. Biochim Biophys Acta. 1990;1049(2):99–125.

    Article  PubMed  Google Scholar 

  14. Dominski Z, Kole R. Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc Natl Acad Sci U S A. 1993;90(18):8673–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Veltrop M, Aartsma-Rus A. Antisense-mediated exon skipping: taking advantage of a trick from Mother Nature to treat rare genetic diseases. Exp Cell Res. 2014;325(1):50–5.

    Article  CAS  PubMed  Google Scholar 

  16. Turczynski S, Titeux M, Pironon N, Hovnanian A. Antisense-mediated exon skipping to reframe transcripts. Methods Mol Biol. 2012;867:221–38.

    Article  CAS  PubMed  Google Scholar 

  17. Arechavala-Gomeza V, Anthony K, Morgan J, Muntoni F. Antisense oligonucleotide-mediated exon skipping for Duchenne muscular dystrophy: progress and challenges. Curr Gene Ther. 2012;12(3):152–60.

    Article  CAS  PubMed  Google Scholar 

  18. Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA, Sitsen JM, Aartsma-Rus A, van Ommen GJ, Buyse G, Darin N, Verschuuren JJ, Campion GV, de Kimpe SJ, van Deutekom JC. Systemic administration of PRO051 in Duchenne’s muscular dystrophy. N Engl J Med. 2011;364(16):1513–22.

    Google Scholar 

  19. van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, den Dunnen JT, Koop K, van der Kooi AJ, Goemans NM, de Kimpe SJ, Ekhart PF, Venneker EH, Platenburg GJ, Verschuuren JJ, van Ommen GJ. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med. 2007;357(26):2677–86.

    Article  PubMed  Google Scholar 

  20. Voit T, Topaloglu H, Straub V, Muntoni F, Deconinck N, Campion G, De Kimpe SJ, Eagle M, Guglieri M, Hood S, Liefaard L, Lourbakos A, Morgan A, Nakielny J, Quarcoo N, Ricotti V, Rolfe K, Servais L, Wardell C, Wilson R, Wright P, Kraus JE. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol. 2014;13(10):987–96.

    Article  CAS  PubMed  Google Scholar 

  21. Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P Saoud JB, Kaye EM. Eteplirsen study group 2013, ‘Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74:637–47.

    Google Scholar 

  22. Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM, Mercuri E. Eteplirsen Study Group and Telethon Foundation DMD Italian Network. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016;79(2):257–71.

    Google Scholar 

  23. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, Norris DA, Bennett CF, Bishop KM. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016;86(10):890–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Haché M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. Intrathecal injections in children with spinal muscular atrophy: Nusinersen clinical trial experience. J Child Neurol. 2016;31(7):899–906.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bacchi N, Casarosa S, Denti MA. Splicing-correcting therapeutic approaches for retinal dystrophies: where endogenous gene regulation and specificity matter. Invest Ophthalmol Vis Sci. 2014;55:3285–94.

    Article  CAS  PubMed  Google Scholar 

  26. Pérez B, Vilageliu L, Grinberg D, Desviat LR. Antisense mediated splicing modulation for inherited metabolic diseases: challenges for delivery. Nucleic Acid Ther. 2014;24(1):48–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Porensky P, Burges A. Antisense oligonucleotides for the treatment of spinal muscular atrophy. Hum Gene Ther. 2013;24:489–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Siva K, Covello G, Denti MA. Exon-skipping antisense oligonucleotides to correct missplicing in neurogenetic diseases. Nucleic Acid Ther. 2014;24:69–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Disterer P, Khoo B. Antisense-mediated exon-skipping to induce gene knockdown. Methods Mol Biol. 2012;867:289–305.

    Article  CAS  PubMed  Google Scholar 

  30. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discovery. 2013;12:847–65.

    Article  CAS  PubMed  Google Scholar 

  31. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges MR. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368:1685–94.

    Article  CAS  PubMed  Google Scholar 

  32. Van Der Ree MH, Van Der Meer AJ, De Bruijne J, Maan R, Van Vliet A, Welzel TM, Zeuzem S, Lawitz EJ, Rodriguez-Torres M, Kupcova V, Wiercinska-Drapalo A, Hodges MR, Janssen HLA, Reesink HW. Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients. Antiviral Res. 2014;111:53–9.

    Article  PubMed  CAS  Google Scholar 

  33. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494–8.

    Article  CAS  PubMed  Google Scholar 

  34. Garba AO, Mousa SA. Bevasiranib for the treatment of wet, age-related macular degeneration. Ophthalmol Eye Dis. 2010;2:75–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Singerman L. Combination therapy using the small interfering RNA bevasiranib. Retina. 2009;29:S49–50.

    Article  PubMed  Google Scholar 

  36. Cho WG, Albuquerque RJ, Kleinman ME, Tarallo V, Greco A, Nozaki M, Green MG, Baffi JZ, Ambati BK, De Falco M, Alexander JS, Brunetti A, De Falco S, Ambati J. Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth. Proc Natl Acad Sci U S A. 2009;106(17):7137–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, Albuquerque RJ, Yamasaki S, Itaya M, Pan Y, Appukuttan B, Gibbs D, Yang Z, Karikó K, Ambati BK, Wilgus TA, DiPietro LA, Sakurai E, Zhang K, Smith JR, Taylor EW, Ambati J. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008;452:591–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sullenger BA, Nair S. From the RNA world to the clinic. Science. 2016;352(6292):1417–20.

    Article  CAS  PubMed  Google Scholar 

  39. Henry JC, Azevedo-Pouly AC, Schmittgen TD. MicroRNA replacement therapy for cancer. Pharm Res. 2011;28(12):3030–42.

    Article  CAS  PubMed  Google Scholar 

  40. Bouchie A. First microRNA mimic enters clinic. Nat Biotechnol. 2013;31:577.

    Article  CAS  PubMed  Google Scholar 

  41. Reid G, Kao SC, Pavlakis N, Brahmbhatt H, MacDiarmid J, Clarke S, Boyer M, van Zandwijk N. Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer. Epigenomics. 2016;8(8):1079–85.

    Article  CAS  PubMed  Google Scholar 

  42. Nielsen PE. Sequence-selective targeting of duplex DNA by peptide nucleic acids. Curr Opin Mol Ther. 2010;12:184–91.

    CAS  PubMed  Google Scholar 

  43. Paramasivam M, Cogoi S, Filichev VV, Bomholt N, Pedersen EB, Xodo LE. Purine twisted-intercalating nucleic acids: a new class of anti-gene molecules resistant to potassium-induced aggregation. Nucleic Acids Res. 2008;36:3494–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zaghloul EM, Madsen AS, Moreno PM, Oprea II, El-Andaloussi S, Bestas B, Gupta P, Pedersen EB, Lundin KE, Wengel J, Smith CI. Optimizing anti-gene oligonucleotide “Zorro-LNA” for improved strand invasion into duplex DNA. Nucleic Acids Res. 2011;39:1142–54.

    Article  CAS  PubMed  Google Scholar 

  45. Kayali R, Bury F, Ballard M, Bertoni C. Site-directed gene repair of the dystrophin gene mediated by PNA–ssODNs. Hum Mol Genet. 2010;19:3266–81.

    Article  CAS  PubMed  Google Scholar 

  46. Lonkar P, Kim KH, Kuan JY, Chin JY, Rogers FA, Knauert MP, Kole R, Nielsen PE, Glazer PM. Targeted correction of a thalassemia-associated betaglobin mutation induced by pseudo-complementary peptide nucleic acids. Nucleic Acids Res. 2009;37:3635–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Boulware SB, Christensen LA, Thames H, Coghlan L, Vasquez KM, Finch RA. Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer. Mol Carcinog. 2014;53(9):744–52.

    Article  CAS  PubMed  Google Scholar 

  48. St Laurent G, Wahlestedt C, Kapranov P. The landscape of long noncoding RNA classification. Trends Genet. 2015;31:239–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ng EW, Shima DT, Calias P, Cunningham ET Jr, Guyer DR, Adamis AP. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discovery. 2006;5:123–32.

    Article  CAS  PubMed  Google Scholar 

  50. Ruckman J, Green LS, Beeson J, Waugh S, Gillette WL, Henninger DD, Claesson-Welsh L, Janjić N. 2′-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain. J Biol Chem. 1998;273:20556–67.

    Article  CAS  PubMed  Google Scholar 

  51. Lincoff AM, Mehran R, Povsic TJ, Zelenkofske SL, Huang Z, Armstrong PW, Steg PG, Bode C, Cohen MG, Buller C, Laanmets P, Valgimigli M, Marandi T, Fridrich V, Cantor WJ, Merkely B, Lopez-Sendon J, Cornel JH, Kasprzak JD, Aschermann M, Guetta V, Morais J, Sinnaeve PR, Huber K, Stables R, Sellers MA, Borgman M, Glenn L, Levinson AI, Lopes RD, Hasselblad V, Becker RC, Alexander JH. REGULATE-PCI investigators 2016, ‘Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet 2016;387(10016):349–56.

    Google Scholar 

  52. Povsic TJ, Vavalle JP, Aberle LH, Kasprzak JD, Cohen MG, Mehran R, Bode C, Buller CE, Montalescot G, Cornel JH, Rynkiewicz A, Ring ME, Zeymer U, Natarajan M, Delarche N, Zelenkofske SL, Becker RC, Alexander JH, Investigators RADAR. A phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J. 2013;34(31):2481–9.

    Article  CAS  PubMed  Google Scholar 

  53. Drolet DW, Green LS, Gold L, Janjic N. Fit for the eye: aptamers in ocular disorders. Nucleic Acid Ther. 2016;26(3):127–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jaffe GJ, Eliott D, Wells JA, Prenner JL, Papp A, Patel S. A phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2016;123(1):78–85.

    Article  PubMed  Google Scholar 

  55. Zhou J, Rossi JJ. Cell-type-specific, aptamer functionalized agents for targeted disease therapy. Mol Ther Nucleic Acids. 2014;3:e169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sioud M. Deciphering the code of innate immunity recognition of siRNAs. Methods Mol Biol. 2009;487:41–59.

    CAS  PubMed  Google Scholar 

  57. Goubau D, Schlee M, Deddouche S, Pruijssers AJ, Zillinger T, Goldeck M, Schuberth C, Van der Veen AG, Fujimura T, Rehwinkel J, Iskarpatyoti JA, Barchet W, Ludwig J, Dermody TS, Hartmann G, Reis e Sousa C. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5-diphosphates. Nature 2014;514:372–5.

    Google Scholar 

  58. Kandimalla ER, Bhagat L, Wang D, Yu D, Sullivan T, La Monica N, Agrawal S. Design, synthesis and biological evaluation of novel antagonist compounds of toll-like receptors 7, 8 and 9. Nucleic Acids Res. 2013;41:3947–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Krieg AM. CpG still rocks! Update on an accidental drug. Nucleic Acid Ther. 2012;22:77–89.

    CAS  PubMed  Google Scholar 

  60. Deleavey GF, Damha MJ. Designing chemically modified oligonucleotides for targeted gene silencing. Chem Biol. 2012;19:937–54.

    Article  CAS  PubMed  Google Scholar 

  61. Saleh AF, Arzumanov AA, Gait MJ. Overview of alternative oligonucleotide chemistries for exon skipping. Methods Mol Biol. 2012;867:365–78.

    Article  CAS  PubMed  Google Scholar 

  62. Sharma VK, Watts JK. Oligonucleotide therapeutics: chemistry, delivery and clinical progress. Future Med Chem. 2015;16:221–42.

    Google Scholar 

  63. Watts JK, Corey DR. Silencing disease genes in the laboratory and the clinic. J Pathol. 2012;226:365–79.

    Article  CAS  PubMed  Google Scholar 

  64. Eckstein F. Phosphorothioates, essential components of therapeutic oligonucleotides. Nucleic Acid Ther. 2014;24:374–87.

    Article  CAS  PubMed  Google Scholar 

  65. Crooke ST, Geary RS. Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B. Br J Clin Pharmacol. 2013;76(2013):269–76.

    Article  CAS  PubMed  Google Scholar 

  66. Crooke ST. Progress in antisense technology. Annu Rev Med. 2004;55:61–95.

    Article  CAS  PubMed  Google Scholar 

  67. Burnett JC, Rossi JJ. RNA-based therapeutics: current progress and future prospects. Chem Biol. 2012;19:60–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, Krainer AR. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 2010;24:1634–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jarver P, O’Donovan L, Gait MJ. A chemical view of oligonucleotides for exon skipping and related drug applications. Nucleic Acid Ther. 2014;24:37–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Egholm M, Buchardt O, Christensen L, Behrens C, Freier SM, Driver DA, Berg RH, Kim SK, Norden B, Nielsen PE. PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules. Nature 1999;365:66ì–568.

    Google Scholar 

  71. Nielsen PE, Egholm M, Berg RH, Buchardt O. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science. 1991;254:1497–500.

    Article  CAS  PubMed  Google Scholar 

  72. Ensen KK, Orum H, Nielsen PE, Norden B. Kinetics for hybridization of peptide nucleic acids (PNA) with DNA and RNA studied with the BIAcore technique. Biochemistry. 1997;36:5072–7.

    Article  Google Scholar 

  73. Amantana A, Iversen PL. Phamacokinetics and biodistribution of phosphorodiamidate morpholino antisense oligomers. Curr Opin Pharmacol. 2005;5:550–5.

    Article  CAS  PubMed  Google Scholar 

  74. Summerton J, Weller D. Morpholino antisense oligomers: design, preparation, and properties. Antisense Nucleic Acid Drug Dev. 1997;7:187–95.

    Article  CAS  PubMed  Google Scholar 

  75. Campbell MA, Wengel J. Locked vs. unlocked nucleic acids (LNA vs. UNA): contrasting structures work towards common therapeutic goals. Chem Soc Rev. 2011;40:5680–9.

    Article  CAS  PubMed  Google Scholar 

  76. Pallan PS, Allerson CR, Berdeja A, Seth PP, Swayze EE, Prakash TP, Egli M. Structure and nuclease resistance of 2′,4′-constrained 2′-O-methoxyethyl (cMOE) and 2′-O-ethyl (cEt) modified DNAs. Chem Commun. 2012;48(66):8195–7.

    Article  CAS  Google Scholar 

  77. Renneberg D, Leumann CJ. Watson-Crick basepairing properties of tricyclo-DNA. J Am Chem Soc. 2002;124:5993–6002.

    Article  CAS  PubMed  Google Scholar 

  78. Aartsma-Rus A, Kaman WE, Bremmer-Bout M, Janson AA, den Dunnen JT, van Ommen GJ, van Deutekom JC. Comparative analysis of antisense oligonucleotide analogs for targeted DMD exon 46 skipping in muscle cells. Gene Ther 2004;11:1391–8.

    Google Scholar 

  79. Goyenvalle A, Griffith G, Babbs A, El Andaloussi S, Ezzat K, Avril A, Dugovic B, Chaussenot R, Ferry A, Voit T, Amthor H, Bühr C, Schürch S, Wood MJ, Davies KE, Vaillend C, Leumann C, Garcia L. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat Med. 2015;21:270–5.

    CAS  PubMed  Google Scholar 

  80. Elayadi AN, Braasch DA, Corey DR. Implications of high-affinity hybridization by locked nucleic acid oligomers for inhibition of human telomerase. Biochemistry. 2002;41:9973–81.

    Article  CAS  PubMed  Google Scholar 

  81. Arzumanov A, Walsh AP, Rajwanshi VK, Kumar R, Wengel J, Gait MJ. Inhibition of HIV-1 Tat-dependent trans-activation by steric block chimeric 2′-O-methyl/LNA oligoribonucleotides. Biochemistry. 2001;40:14645–54.

    Article  CAS  PubMed  Google Scholar 

  82. Fabani M, Gait MJ. miR-122 targeting with LNA/2’-O-methyl oligonucleotide mixmers, peptide nucleic acids (PNA), and PNA peptide conjugates. RNA J. 2008;14:336–46.

    Article  CAS  Google Scholar 

  83. Kang L, Wang RF, Yan P, Liu M, Zhang CL, Yu MM, Cui YG, Xu XJ. Noninvasive visualization of RNA delivery with 99mTc-radiolabeled small-interference RNA in tumor xenografts. J Nucl Med. 2010;51:978–86.

    Article  CAS  PubMed  Google Scholar 

  84. Komarova Y, Malik AB. Regulation of endothelial permeability via paracellular and transcellular transport pathways. Annu Rev Physiol. 2010;72:463–93.

    Article  CAS  PubMed  Google Scholar 

  85. Shannahan JH, Bai W, Brown JM. Implications of scavenger receptors in the safe development of nanotherapeutics. Receptors Clin Invest. 2015;2:e811.

    Google Scholar 

  86. Tseng YC, Mozumdar S, Huang L. Lipid-based systemic delivery of siRNA. Adv Drug Deliv Rev. 2009;61:721–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2015;99:28–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Yang Q, Jones SW, Parker CL, Zamboni WC, Bear JE, Lai SK. Evading immune cell uptake and clearance requires PEG grafting at densities substantially exceeding the minimum for brush conformation. Mol Pharm. 2014;11:1250–8.

    Article  CAS  PubMed  Google Scholar 

  89. Benimetskaya L, Loike JD, Khaled Z, Loike G, Silverstein SC, Cao L, Khoury J, Cai TQ, Stein CA. Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein. Nat Med. 1997;3:414–20.

    Article  CAS  PubMed  Google Scholar 

  90. Yu X, Guo C, Fisher PB, Subjeck JR, Wang XY. Scavenger receptors: emerging roles in cancer biology and immunology. Adv Cancer Res. 2015;128:309–64.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Ezzat K, Aoki Y, Koo T, McClorey G, Benner L, Coenen-Stass A, O’Donovan L, Lehto T, Garcia-Guerra A, Nordin J, Saleh AF, Behlke M, Morris J, Goyenvalle A, Dugovic B, Leumann C, Gordon S, Gait MJ, El-Andaloussi S, Wood MJA. Self-assembly into nanoparticles is essential for receptor mediated uptake of therapeutic antisense oligonucleotides. NANO Lett. 2015;15:4364–73.

    Google Scholar 

  92. Butler M, Crooke RM, Graham MJ, Lemonidis KM, Lougheed M, Murray SF, Witchell D, Steinbrecher U, Bennett CF. Phosphorothioate oligodeoxynucleotides distribute similarly in class A scavenger receptor knockout and wild-type mice. J Pharmacol Exp Ther. 2000;292:489–96.

    CAS  PubMed  Google Scholar 

  93. Butler M, Stecker K, Bennett CF. Cellular distribution of phosphorothioate oligodeoxynucleotides in normal rodent tissues. Lab Invest. 1997;77:379–88.

    CAS  PubMed  Google Scholar 

  94. Godfrey C, Desviat LR, Smedsrod B, Piétri-Rouxel F, Denti MA, Disterer P, Lorain S, Nogales-Gadea G, Sardone V, Anwar R, El Andaloussi S, Lehto T, Khoo B, Brolin Hjortkjaer C, van Roon-Mom WMC, Goyenvalle A, Aartsma-Rus A, Arechavala-Gomeza V. Delivery is key: lessons learnt from developing splice switching antisense therapy. EMBO Mol Med. 2016 (accepted).

    Google Scholar 

  95. Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008;88:451–87.

    Article  CAS  PubMed  Google Scholar 

  96. Dirin M, Winkler J. Influence of diverse chemical modifications on the ADME characteristics and toxicology of antisense oligonucleotides. Expert Opin Biol Ther. 2013;13:875–88.

    Article  CAS  PubMed  Google Scholar 

  97. Geary RS, Norris D, Yu R, Bennett CF. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev. 2015;87:46–51.

    Article  CAS  PubMed  Google Scholar 

  98. Geary RS. Antisense oligonucleotide pharmacokinetics and metabolism. Exp Opin Drug Metab Toxicol. 2009;5:381–91.

    Article  CAS  Google Scholar 

  99. Evers MM, Toonen LJ, van Roon-Mom WM. Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv Drug Deliv Rev. 2015;87:90–103.

    Article  CAS  PubMed  Google Scholar 

  100. Alyautdin R, Khalin I, Nafeeza MI, Haron MH, Kuznetsov D. Nanoscale drug delivery systems and the blood-brain barrier. Int J Nanomed. 2014;9:795–811.

    CAS  Google Scholar 

  101. Boisguerin P, Deshayes S, Gait MJ, O’Donovan L, Godfrey C, Betts CA, Wood MJ, Lebleu B. Delivery of therapeutic oligonucleotides with cell penetrating peptides. Adv Drug Deliv Rev. 2015;87:52–67.

    Article  CAS  PubMed  Google Scholar 

  102. Du L, Kayali R, Bertoni C, Fike F, Hu H, Iversen PL, Gatti RA. Arginine-rich cell-penetrating peptide dramatically enhances AMO-mediated ATM aberrant splicing correction and enables delivery to brain and cerebellum. Hum Mol Genet. 2011;20:3151–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Alam MR, Ming X, Dixit V, Fisher M, Chen X, Juliano RL. The biological effect of an antisense oligonucleotide depends on its route of endocytosis and trafficking. Oligonucleotides. 2010;20:103–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Koller E, Vincent TM, Chappell A, De S, Manoharan M, Bennett CF. Mechanisms of single-stranded phosphorothioate modified antisense oligonucleotide accumulation in hepatocytes. Nucleic Acids Res. 2011;39:4795–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Juliano RL, Carver K. Cellular uptake and intracellular trafficking of oligonucleotides. Adv Drug Deliv Rev. 2015;87:35–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lorenz P, Misteli T, Baker BF, Bennett CF, Spector DL. Nucleocytoplasmic shuttling: a novel in vivo property of antisense phosphorothioate oligodeoxynucleotides. Nucleic Acids Res. 2000;28:582–92.

    Google Scholar 

  107. Wagenaar TR, Tolstykh T, Shi C, Jiang L, Zhang J, Li Z, Yu Q, Qu H, Sun F, Cao H, Pollard J, Dai S, Gao Q, Zhang B, Arlt H, Cindhuchao M, Hoffmann D, Light M, Jensen K, Hopke J, Newcombe R, Garcia-Echeverria C, Winter C, Zabludoff S, Wiederschain D. Identification of the endosomal sorting complex required for transport-I (ESCRT-I) as an important modulator of anti-miR uptake by cancer cells. Nucleic Acids Res. 2015;43:1204–15.

    Article  CAS  PubMed  Google Scholar 

  108. Sahay G, Querbes W, Alabi C, Eltoukhy A, Sarkar S, Zurenko C, Karagiannis E, Love K, Chen D, Zoncu R, Buganim Y, Schroeder A, Langer R, Anderson DG. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat Biotechnol. 2013;31:653–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zelphati O, Szoka FC Jr. Mechanism of oligonucleotide release from cationic liposomes. Proc Natl Acad Sci U S A. 1996;93:11493–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Xue HY, Liu S, Wong HL. Nanotoxicity: a key obstacle to clinical translation of siRNA-based nanomedicine. Nanomedicine 2014a;9:295–312.

    Google Scholar 

  111. Xue W, Dahlman JE, Tammela T, Khan OF, Sood S, Dave A, Cai W, Chirino LM, Yang GR, Bronson R, Crowley DG, Sahay G, Schroeder A, Langer R, Anderson DG, Jacks T. Small RNA combination therapy for lung cancer. Proc Natl Acad Sci U S A. 2014b;111:e3553–61.

    Google Scholar 

  112. Tam YY, Chen S, Cullis PR. Advances in lipid nanoparticles for siRNA delivery. Pharmaceutics. 2013;5:498–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Thi EP, Mire CE, Ursic-Bedoya R, Geisbert JB, Lee AC, Agans KN, Robbins M, Deer DJ, Fenton KA, MacLachlan I, Geisbert TW. Marburg virus infection in nonhuman primates: therapeutic treatment by lipid-encapsulated siRNA. Sci Trans Med. 2014;6:250ra116.

    Google Scholar 

  114. Abes S, Moulton HM, Clair P, Prevot P, Youngblood DS, Wu RP, Iversen PL, Lebleu B. Vectorization of morpholino oligomers by the (R-Ahx-R)(4) peptide allows efficient splicing correction in the absence of endosomolytic agents. J Controlled Release. 2006;116:304–13.

    Google Scholar 

  115. Burrer R, Neuman BW, Ting JPC, Stein DA, Moulton HM, Iversen PL, Kuhn P, Buchmeier MJ. Antiviral effects of antisense morpholino oligomers in murine coronavirus infection models. J Virol. 2007;81:5637–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Amantana A, Moulton HM, Cate ML, Reddy MT, Whitehead T, Hassinger JN, Youngblood DS, Iversen PL. Pharmacokinetics, biodistribution, stability and toxicity of a cell-penetrating peptide-morpholino oligomer conjugate. Bioconjug Chem. 2007;18:1325–31.

    Article  CAS  PubMed  Google Scholar 

  117. Lehto T, Castillo Alvarez A, Gauck S, Gait MJ, Coursindel T, Wood MJ, Lebleu B, Boisguerin P. Cellular trafficking determines the exon skipping activity of Pip6a-PMO in mdx skeletal and cardiac muscle cells. Nucleic Acids Res. 2014;42:3207–17.

    Article  CAS  PubMed  Google Scholar 

  118. Heald AE, Charleston JS, Iversen PL, Warren TK, Saoud JB, Al-Ibrahim M, Wells J, Warfield KL, Swenson DL, Welch LS, Sazani P, Wong M, Berry D, Kaye EM, Bavari S. AVI-7288 for marburg virus in nonhuman primates and humans. N Engl J Med. 2015;373:339–48.

    Article  CAS  PubMed  Google Scholar 

  119. Li YF, Morcos PA. Design and synthesis of dendritic molecular transporter that achieves efficient in vivo delivery of morpholino antisense oligo. Bioconjug Chem. 2008;19:1464–70.

    Article  CAS  PubMed  Google Scholar 

  120. Ferguson DP, Dangott LJ, Lightfoot JT. Lessons learned from vivo-morpholinos: How to avoid vivo-morpholino toxicity. Biotechniques. 2014;56:251–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gallego-Villar L, Viecelli HM, Perez B, Harding CO, Ugarte M, Thony B, Desviat LR. A sensitive assay system to test antisense oligonucleotides for splice suppression therapy in the mouse liver. Mol Ther Nucleic Acids. 2014;3:e193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ming X, Laing B. Bioconjugates for targeted delivery of therapeutic oligonucleotides. Adv Drug Deliv Rev. 2015;87:81–9.

    Google Scholar 

  123. Nair JK, Willoughby JL, Chan A, Charisse K, Alam MR, Wang Q, Hoekstra M, Kandasamy P, Kel’in AV, Milstein S, Taneja N, O’Shea J, Shaikh S, Zhang L, van der Sluis RJ, Jung ME, Akinc A, Hutabarat R, Kuchimanchi S, Fitzgerald K, Zimmermann T, van Berkel TJ, Maier MA, Rajeev KG, Manoharan M. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014;136:16958–61.

    Google Scholar 

  124. Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, Schmidt K, Zhao C, Aghajan M, Murray HF, Riney S, Booten SL, Murray SF, Gaus H, Crosby J, Lima WF, Guo S, Monia BP, Swayze EE, Seth PP. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 2014;42:8796–807.

    Google Scholar 

  125. Prakash TP, Yu J, Migawa MT, Kinberger GA, Wan WB, Ostergaard ME, Carty RL, Vasquez G, Low A, Chappell A, Schmidt K, Aghajan M, Crosby J, Murray HM, Booten SL, Hsiao J, Soriano A, Machemer T, Cauntay P, Burel SA, Murray SF, Gaus H, Graham MJ, Swayze EE, Seth PP. Comprehensive structure-activity relationship of triantennary N-acetylgalactosamine conjugated antisense oligonucleotides for targeted delivery to hepatocytes. J Med Chem. 2016;59:2718–33.

    Article  CAS  PubMed  Google Scholar 

  126. Watanabe A, Nakajima M, Kasuya T, Onishi R, Kitade N, Mayumi K, Ikehara T, Kugimiya A. Comparative characterization of hepatic distribution and mRNA reduction of antisense oligonucleotides conjugated with triantennary N-acetyl galactosamine and lipophilic ligands targeting apolipoprotein B. J Pharmacol Exp Ther. 2016;357:320–30.

    Article  CAS  PubMed  Google Scholar 

  127. Dassie JP, Giangrande PH. Current progress on aptamer-targeted oligonucleotide therapeutics. Ther Deliv. 2013;4:1527–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Yu RZ, Kim TW, Hong A, Watanabe TA, Gaus HJ, Geary RS. Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100. Drug Metab Dispos. 2007;35(3):460–8.

    Article  CAS  PubMed  Google Scholar 

  129. Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford M, McCulley C, Popplewell L, Graham IR, Dickson G, Wood MJ, Wells DJ, Wilton SD, Kole R, Straub V, Bushby K, Sewry C, Morgan JE, Muntoni F. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 2009;8(10):918–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Southwell AL, Skotte NH, Bennett CF, Hayden MR. Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases. Trends Mol Med. 2012;18:634–43.

    Article  CAS  PubMed  Google Scholar 

  131. Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K, Ostrow LW, Schoenfeld D, Macklin EA, Norris DA, Manousakis G, Crisp M, Smith R, Bennett CF, Bishop KM, Cudkowicz ME. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013;12:435–42.

    Google Scholar 

  132. Dhuria SV, Hanson LR, Frey WH 2nd. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci. 2010;99:1654–73.

    Article  CAS  PubMed  Google Scholar 

  133. Stein-Streilein J. Immune regulation and the eye. Trends Immunol. 2008;29:548–54.

    Article  CAS  PubMed  Google Scholar 

  134. Thrimawithana TR, Young S, Bunt CR, Green C, Alany RG. Drug delivery to the posterior segment of the eye. Drug Discovery Today. 2011;16:270–7.

    Article  CAS  PubMed  Google Scholar 

  135. Leeds JM, Henry SP, Truong L, Zutshi A, Levin AA, Kornbrust D. Pharmacokinetics of a potential human cytomegalovirus therapeutic, a phosphorothioate oligonucleotide, after intravitreal injection in the rabbit. Drug Metab Dispos. 1997;25(8):921–6.

    Google Scholar 

  136. Cursiefen C, Bock F, Horn FK, Kruse FE, Seitz B, Borderie V, Fruh B, Thiel MA, Wilhelm F, Geudelin B, Descohand I, Steuhl KP, Hahn A, Meller D. GS-101 antisense oligonucleotide eye drops inhibit corneal neovascularization: interim results of a randomized phase II trial. Ophthalmology. 2009;116:1630–7.

    Article  PubMed  Google Scholar 

  137. Cursiefen C, Viaud E, Bock F, Geudelin B, Ferry A, Kadlecova P, Levy M, Al Mahmood S, Colin S, Thorin E, Majo F, Frueh B, Wilhelm F, Meyer-Ter-Vehn T, Geerling G, Bohringer D, Reinhard T, Meller D, Pleyer U, Bachmann B, Seitz B. Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study. Ophthalmology. 2014;121:1683–92.

    Article  PubMed  Google Scholar 

  138. Berdugo M, Valamanesh F, Andrieu C, Klein C, Benezra D, Courtois Y, Behar-Cohen F. Delivery of antisense oligonucleotide to the cornea by iontophoresis. Antisense Nucleic Acid Drug Dev. 2003;13:107–14.

    Article  CAS  PubMed  Google Scholar 

  139. Bochot A, Mashhour B, Puisieux F, Couvreur P, Fattal E. Comparison of the ocular distribution of a model oligonucleotide after topical instillation in rabbits of conventional and new dosage forms. J Drug Target. 1998;6:309–13.

    Article  CAS  PubMed  Google Scholar 

  140. Andrieu-Soler C, Doat M, Halhal M, Keller N, Jonet L, BenEzra D, Behar-Cohen F. Enhanced oligonucleotide delivery to mouse retinal cells using iontophoresis. Mol Vis. 2006;26(12):1098–107.

    Google Scholar 

  141. Pescina S, Antopolsky M, Santi P, Nicoli S, Murtomäki L. Effect of iontophoresis on the in vitro trans-scleral transport of three single stranded oligonucleotides. Eur J Pharm Sci. 2013;49(2):142–7.

    Article  CAS  PubMed  Google Scholar 

  142. Frazier KS. Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist’s perspective. Toxicol Pathol. 2015;43:78–89.

    Article  PubMed  CAS  Google Scholar 

  143. Lindow M, Vornlocher HP, Riley D, Kornbrust DJ, Burchard J, Whiteley LO, Kamen J, Thompson JD, Nochur S, Younis H, Bartz S, Parry J, Ferrari N, Henry SP, Levin AA. Assessing unintended hybridization-induced biological effects of oligonucleotides. Nat Biotechnol. 2012;30:920–3.

    Article  CAS  PubMed  Google Scholar 

  144. Crooke ST, Baker BF, Kwoh TJ, Cheng W, Schulz DJ, Xia S, Salgado N, Bui HH, Hart CE, Burel SA, Younis HS, Geary RS, Henry SP, Bhanot S. Integrated safety assessment of 2′-O-Methoxyethyl chimeric antisense oligonucleotides in nonhuman primates and healthy human volunteers. Mol Ther. 2016;24(10):1771–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Engelhardt JA. Comparative renal toxicopathology of antisense oligonucleotides. Nucleic Acid Ther. 2016;26:199–209.

    Article  CAS  PubMed  Google Scholar 

  146. Kakiuchi-Kiyota S, Koza-Taylor PH, Mantena SR, Nelms LF, Enayetallah AE, Hollingshead BD, Burdick AD, Reed LA, Warneke JA, Whiteley LO, Ryan AM, Mathialagan N. Comparison of hepatic transcription profiles of locked ribonucleic acid antisense oligonucleotides: evidence of distinct pathways contributing to non-target mediated toxicity in mice. Toxicol Sci. 2014;138:234–48.

    Article  CAS  PubMed  Google Scholar 

  147. Burdick AD, Sciabola S, Srinivasa R, Mantena BD, Hollingshead T, Stanton R, Warneke JA, Zeng M, Martsen E, Medvedev A, Makarov SS, Reed LA, Davis JW II, Whitely LO. Sequence motifs associated with hepatotoxicity of locked nucleic acid-modified antisense oligonucleotides. Nucleic Acids Res. 2014;42:1–10.

    Article  CAS  Google Scholar 

  148. van Poelgeest EP, Swart RM, Betjes MG, Moerland M, Weening JJ, Tessier Y, Hodges MR, Levin AA, Burggraaf J. Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9. Am J Kidney Dis. 2013;62:796–800.

    Article  PubMed  CAS  Google Scholar 

  149. Herrington WG, Talbot DC, Lahn MM, Brandt JT, Callies S, Nagle R, Winearls CG, Roberts IS. Association of long-term administration of the survivin mRNA-targeted antisense oligonucleotide LY2181308 with reversible kidney injury in a patient with metastatic melanoma. Am J Kidney Dis. 2011;57:300–3.

    Article  CAS  PubMed  Google Scholar 

  150. Martinez T, Wright N, Lopez-Fraga M, Jiménez AI, Pañeda C. Silencing human genetic diseases with oligonucleotidebased therapies. Hum Genet. 2013;132:481–93.

    Google Scholar 

Download references

Acknowledgements

The preparation of this manuscript was supported by a Grant by the Italian Ministry of Health (RF-2011-02347694) to M.A.D.

M.A.D. is member of the Managing Committee of the Cooperation of Science and Technology (COST) Action BM1207: “Networking towards clinical application of antisense-mediated exon skipping.”

Author information

Authors and Affiliations

  1. RNA Biology and Biotechnology Laboratory, Centre for Integrative Biology, University of Trento, Trento, Italy

    Michela Alessandra Denti & Giuseppina Covello

Authors
  1. Michela Alessandra Denti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuseppina Covello
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michela Alessandra Denti .

Editor information

Editors and Affiliations

  1. Department of Translational Medicine, University of Naples Federico II, Naples, Italy

    Nicola Brunetti-Pierri

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Denti, M.A., Covello, G. (2017). Oligonucleotide Therapy. In: Brunetti-Pierri, N. (eds) Safety and Efficacy of Gene-Based Therapeutics for Inherited Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-53457-2_9

Download citation

Publish with us

Policies and ethics

Search

Navigation