Skip to main content
SpringerLink
Log in
Book cover

RNA Technologies and Their Applications pp 285–303Cite as

Antisense Oligonucleotides: Insights from Preclinical Studies and Clinical Trials

  • Chapter
  • First Online:

Part of the book series: RNA Technologies ((RNATECHN))

Abstract

Since the first pioneering studies using antisense oligonucleotides (ASOs) in the late 1970s, thousands of publications followed, demonstrating the remarkableness of antisense action and its enormous application spectrum. In 1998, Fomivirsen (Vitravene) was the first, and to date the only ASO that gained approval by the US Food and Drug Administration (FDA) for intravitreous treatment of cytomegalovirus-induced retinitis in patients with acquired immune deficiency syndrome (AIDS). Meanwhile, efforts regarding ASO research decreased and investigations shifted to other molecules, e.g., small interfering RNAs, because ASO-related problems such as insufficient efficacy and off-target effects are not yet overcome. However, newer studies using ASOs with improved chemistry or approaches combining ASO treatment with other therapies, such as chemotherapy or radiation, might bring ASOs back into the spotlight. This chapter will focus on current in vivo studies and clinical trials of promising ASOs.

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   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
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

Notes

  1. 1.

    All websites mentioned in the text were viewed on July 15th, 2009.

Abbreviations

ApoB-100:

Apolipoprotein B-100

AIDS:

Acquired immune deficiency syndrome

AML:

Acute myeloid leukemia

ASO:

Antisense oligonucleotide

BCL2:

B-cell CLL/lymphoma 2

CLL:

Chronic lymphocytic leukemia

CpG:

Cytosine–guanine dinucleotide

DMD:

Duchenne muscular dystrophy

FDA:

US food and drug administration

FH:

Familial hypercholesterolemia

HBV:

Hepatitis B virus

HIV:

Human immunodeficiency virus

IAP:

Inhibitor of apoptosis protein

LDH:

Lactate dehydrogenase

LNA:

Locked nucleic acid

LDL-c:

Low density lipoprotein cholesterol

miRNA:

Micro ribonucleic acid

miR-122:

MicroRNA-122

NSCLC:

Nonsmall cell lung cancer

PCa:

Prostate cancer

PMO:

Phosphoroamidate morpholino oligomer

PNA:

Peptide nucleic acid

PPMO:

Peptide-conjugated phosphoroamidate morpholino oligomer

PS:

Phosphorothioate

TGFB2:

Transforming growth factor, β 2

XIAP:

X-linked inhibitor of apoptosis

2′-OMe:

2′-O-Methyl

2′-MOE:

2′-O-(2′-Methoxy)ethyl

References

  • Aartsma-Rus A, Fokkema I, Verschuuren J et al (2009) Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat 30:293–299

    Article  PubMed  Google Scholar 

  • Advani R, Lum BL, Fisher GA et al (2005) A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-alpha administered as a 24-hour weekly infusion schedule in patients with advanced cancer. Invest New Drugs 23:467–477

    Article  PubMed  CAS  Google Scholar 

  • Agrawal S, Kandimalla ER (2001) Antisense and/or immunostimulatory oligonucleotide therapeutics. Curr Cancer Drug Targets 1:197–209

    Article  PubMed  CAS  Google Scholar 

  • Agrawal S, Kandimalla ER (2003) Modulation of toll-like receptor 9 responses through synthetic immunostimulatory motifs of DNA. Ann NY Acad Sci 1002:30–42

    Article  PubMed  CAS  Google Scholar 

  • Altieri DC (2003) Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22:8581–8589

    Article  PubMed  CAS  Google Scholar 

  • Anderson EM, Miller P, Ilsley D et al (2006) Gene profiling study of G3139- and Bcl-2-targeting siRNAs identifies a unique G3139 molecular signature. Cancer Gene Ther 13:406-414

    Article  PubMed  CAS  Google Scholar 

  • Bates PJ, Laber DA, Miller DM et al (2009) Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp Mol Pathol 86:151–164

    Article  PubMed  CAS  Google Scholar 

  • Bedikian AY, Millward M, Pehamberger H et al (2006) Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol 24:4738–4745

    Article  PubMed  CAS  Google Scholar 

  • Bogdahn U, Schneider T, Oliushine V et al (2009) Randomized, active-controlled phase IIb study with trabedersen (AP 12009) in recurrent or refractory high-grade glioma patients: Basis for phase III endpoints. J Clin Oncol 27:2037

    Google Scholar 

  • Call JA, Eckhardt SG, Camidge DR (2008) Targeted manipulation of apoptosis in cancer treatment. Lancet Oncol 9:1002–1011

    Article  PubMed  CAS  Google Scholar 

  • Cao C, Shinohara ET, Li H et al (2005) Clusterin as a therapeutic target for radiation sensitization in a lung cancer model. Int J Radiat Oncol Biol Phys 63:1228–1236

    Article  PubMed  CAS  Google Scholar 

  • Chanan-Khan AA, Niesvizky R, Hohl RJ et al (2009) Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma 50:559–565

    Article  PubMed  CAS  Google Scholar 

  • Chi KN, Eisenhauer E, Fazli L et al (2005) A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2′-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst 97:1287–1296

    Article  PubMed  CAS  Google Scholar 

  • Chi KN, Zoubeidi A, Gleave ME (2008) Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin for the treatment of cancer. Expert Opin Investig Drugs 17:1955–1962

    Article  PubMed  CAS  Google Scholar 

  • Chi KN, Hotte SJ, Yu E et al (2009) Mature results of a randomized phase II study of OGX-011 in combination with docetaxel/prednisone versus docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 27:5012

    Google Scholar 

  • Cooper CL, Davis HL, Angel JB et al (2005) CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 19:1473–1479

    Article  PubMed  CAS  Google Scholar 

  • Crooke ST (2004a) Antisense strategies. Curr Mol Med 4:465–487

    Article  PubMed  CAS  Google Scholar 

  • Crooke ST (2004b) Progress in antisense technology. Annu Rev Med 55:61–95

    Article  PubMed  CAS  Google Scholar 

  • Dapić V, Abdomerović V, Marrington R et al (2003) Biophysical and biological properties of quadruplex oligodeoxyribonucleotides. Nucleic Acids Res 31:2097–2107

    Article  PubMed  Google Scholar 

  • Dean E, Jodrell D, Connolly K et al (2009) Phase I trial of AEG35156 administered as a 7-day and 3-day continuous intravenous infusion in patients with advanced refractory cancer. Clin Oncol 27:1660–1666

    Article  CAS  Google Scholar 

  • Elmén J, Lindow M, Silahtaroglu A et al (2007) Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res 36:1153–1162

    Article  PubMed  Google Scholar 

  • Elmén J, Lindow M, Schütz S et al (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452:896–899

    Article  PubMed  Google Scholar 

  • Fisker N, Westergaard M, Hansen HF et al (2007) Survivin mRNA antagonists using locked nucleic acid, potential for molecular cancer therapy. Nucleosides Nucleotides Nucleic Acids 26:1427–1430

    Article  PubMed  CAS  Google Scholar 

  • Gauvreau GM, Boulet LP, Cockcroft DW et al (2008) Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am J Respir Crit Care Med 177:952–958

    Article  PubMed  CAS  Google Scholar 

  • Gekeler V, Gimmnich P, Hofmann HP et al (2006) G3139 and other CpG-containing immunostimulatory phosphorothioate oligodeoxynucleotides are potent suppressors of the growth of human tumor xenografts in nude mice. Oligonucleotides 16:83–93

    Article  PubMed  CAS  Google Scholar 

  • Goel S, Desai K, Bulgaru A et al (2003) A safety study of a mixed-backbone oligonucleotide (GEM231) targeting the type I regulatory subunit alpha of protein kinase A using a continuous infusion schedule in patients with refractory solid tumors. Clin Cancer Res 9:4069–4076

    PubMed  CAS  Google Scholar 

  • Guimond A, Viau E, Aubé P et al (2008) Advantageous toxicity profile of inhaled antisense oligonucleotides following chronic dosing in non-human primates. Pulm Pharmacol Ther 21:845–854

    Article  PubMed  CAS  Google Scholar 

  • Hansen JB, Fisker N, Westergaard M et al (2008) SPC3042: a proapoptotic survivin inhibitor. Mol Cancer Ther 7:2736–2745

    Article  PubMed  CAS  Google Scholar 

  • Hartmann G, Weeratna RD, Ballas ZK et al (2000) Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 164:1617–1624

    PubMed  CAS  Google Scholar 

  • Henry SP, Giclas PC, Leeds J et al (1997) Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J Pharmacol Exp Ther 281:810–816

    PubMed  CAS  Google Scholar 

  • Jason TLH, Koropatnicka J, Berg RW (2004) Toxicology of antisense therapeutics. Toxicol Appl Pharmacol 201:66–83

    Article  PubMed  CAS  Google Scholar 

  • Jearawiriyapaisarn N, Moulton HM, Buckley B et al (2008) Sustained dystrophin expression induced by peptide-conjugated morpholino oligomers in the muscles of mdx mice. Mol Ther 16:1624–1629

    Article  PubMed  CAS  Google Scholar 

  • Kastelein JJ, Wedel MK, Baker BF et al (2006) Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 114:1729–1735

    Article  PubMed  CAS  Google Scholar 

  • Klasa RJ, Gillum AM, Klem RE et al (2002) Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 12:193–213

    Article  PubMed  CAS  Google Scholar 

  • Kraemer K, Schmidt U, Fuessel S et al (2006) Microarray analyses in bladder cancer cells: inhibition of hTERT expression down-regulates EGFR. Int J Cancer 119:1276–1284

    Article  PubMed  CAS  Google Scholar 

  • Kunze D, Wuttig D, Kausch I et al (2008) Antisense-mediated inhibition of survivin, hTERT and VEGF in bladder cancer cells in vitro and in vivo. Int J Oncol 32:1049–1056

    PubMed  CAS  Google Scholar 

  • Kurreck J (2003) Antisense technologies Improvement through novel chemical modifications. Eur J Biochem 270:1628–1644

    Article  PubMed  CAS  Google Scholar 

  • Lacasse EC, Kandimalla ER, Winocour P et al (2005) Application of XIAP antisense to cancer and other proliferative disorders: development of AEG35156/ GEM640. Ann NY Acad Sci 1058:215–234

    Article  PubMed  CAS  Google Scholar 

  • Lai JC, Benimetskaya L, Santella RM et al (2003) G3139 (oblimersen) may inhibit prostate cancer cell growth in a partially bis-CpG-dependent non-antisense manner. Mol Cancer Ther 2:1031–1043

    PubMed  CAS  Google Scholar 

  • Leonetti C, Biroccio A, D'Angelo C et al (2007) Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer. Prostate 67:1475–1485

    Article  PubMed  CAS  Google Scholar 

  • Lin C, Papadopoulos K, Patnaik A et al (2007) Oblimersen can be administered by subcutaneous (SC) and brief intravenous (IV) infusion: Clinical pharmacokinetics and pharmacodynamics (PK/PD) in patients with advanced cancer. J Clin Oncol 25:14083

    Google Scholar 

  • Marchand C, Pourquier P, Laco GS et al (2002) Interaction of human nuclear topoisomerase I with guanosine quartet-forming and guanosine-rich single-stranded DNA and RNA oligonucleotides. J Biol Chem 277:8906–8911

    Article  PubMed  CAS  Google Scholar 

  • Marcucci G, Moser B, Blum W et al (2007) A phase III randomized trial of intensive induction and consolidation chemotherapy +/− oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old. J Clin Oncol 25:7012

    Article  Google Scholar 

  • Miyake H, Chi KN, Gleave ME (2000) Antisense TRPM-2 oligodeoxynucleotides chemosensitize human androgen-independent PC-3 prostate cancer cells both in vitro and in vivo. Clin Cancer Res 6:1655–1663

    PubMed  CAS  Google Scholar 

  • Monia BP, Lesnik EA, Gonzalez C et al (1993) Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem 268:14514–14522

    PubMed  CAS  Google Scholar 

  • Niepmann M (2009) Activation of hepatitis C virus translation by a liver-specific microRNA. Cell Cycle 8:1473–1477

    Article  PubMed  CAS  Google Scholar 

  • O'Brien S, Moore JO, Boyd TE et al (2007) Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 25:1114–1120

    Article  PubMed  Google Scholar 

  • Oettle H, Hilbig A, Seufferlein T et al (2009) Interim results of the phase I/II study of trabedersen (AP 12009) in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma. J Clin Oncol 27:4619

    Article  Google Scholar 

  • Reed JC (1995) Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol 7:541–546

    Article  PubMed  CAS  Google Scholar 

  • Rubenstein M, Tsui P, Guinan P (2009) Treatment of prostate and breast tumors employing mono- and bi-specific antisense oligonucleotides targeting apoptosis inhibitory proteins clusterin and bcl-2. Med Oncol. doi:10.1007/s12032-009-9254-4

    Google Scholar 

  • Ryan BM, O'Donovan N, Duffy MJ (2009) Survivin: a new target for anti-cancer therapy. Cancer Treat Rev. doi:10.1016/j.ctrv.2009.05.003

    PubMed  Google Scholar 

  • Schimmer AD, Dalili S, Batey RA et al (2006) Targeting XIAP for the treatment of malignancy. Cell Death Differ 13:179–188

    Article  PubMed  CAS  Google Scholar 

  • Schlingensiepen KH, Fischer-Blass B, Schmaus S et al (2008) Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors. Recent Results Cancer Res 177:137–50

    Article  PubMed  CAS  Google Scholar 

  • Spänkuch B, Steinhauser I, Wartlick H et al (2008) Downregulation of Plk1 expression by receptor-mediated uptake of antisense oligonucleotide-loaded nanoparticles. Neoplasia 10:223–234

    PubMed  Google Scholar 

  • Stahel RA, Zangemeister-Wittke U (2003) Antisense oligonucleotides for cancer therapy-an overview. Lung Cancer 41(Suppl 1):S81–88

    Article  PubMed  Google Scholar 

  • Stessl M, Marchetti-Deschmann M, Winkler J et al (2009) A proteomic study reveals unspecific apoptosis induction and reduction of glycolytic enzymes by the phosphorothioate antisense oligonucleotide oblimersen in human melanoma cells. J Proteomics. doi:10.1016/j.jprot.2009.06.001

    PubMed  Google Scholar 

  • Talbot D, Davies J, Callies S et al (2008) First human dose study evaluating safety and pharmacokinetics of LY2181308, an antisense oligonucleotide designed to inhibit survivin. J Clin Oncol 26:3518

    Google Scholar 

  • Talbot D, Davies J, Olsen A et al (2009) Pharmacodynamic (PD) evaluation of LY2181308 in patients with metastatic malignancies. J Clin Oncol 27:3507

    Google Scholar 

  • Tillman LG, Geary RS, Hardee GE (2007) Oral delivery of antisense oligonucleotides in man. J Pharm Sci 97:225–236

    Article  Google Scholar 

  • Tilly H, Coiffier B, Michallet AS et al (2007) Phase I/II study of SPC2996, an RNA antagonist of Bcl-2, in patients with advanced chronic lymphocytic leukaemia (CLL). J Clin Oncol 25:7036

    Google Scholar 

  • van Deutekom JC, Janson AA, Ginjaar IB et al (2007) Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 357:2677–2686

    Article  PubMed  Google Scholar 

  • Vollmer J, Krieg AM (2009) Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists. Adv Drug Deliv Rev 61:195–204

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Liu X, Chen L et al (2009) Tumor delivery of antisense oligomer using trastuzumab within a streptavidin nanoparticle. Eur J Nucl Med Mol Imaging. doi:10.1007/s00259-009-1201-2

    Google Scholar 

  • Warfield KL, Swenson DL, Olinger GG et al (2006) Gene-specific countermeasures against Ebola virus based on antisense phosphorodiamidate morpholino oligomers. PLoS Pathog 2:e1

    Article  PubMed  Google Scholar 

  • Wasan EK, Waterhouse D, Sivak O et al (2002) Plasma protein binding, lipoprotein distribution and uptake of free and lipid-associated BCL-2 antisense oligodeoxynucleotides (G3139) in human melanoma cells. Int J Pharm 241:57–64

    Article  PubMed  CAS  Google Scholar 

  • Wiemer EA (2007) The role of microRNAs in cancer: no small matter. Eur J Cancer 43:1529–1544

    Article  PubMed  CAS  Google Scholar 

  • Yokota T, Lu QL, Partridge T et al (2009) Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs. Ann Neurol 65:667–676

    Article  PubMed  Google Scholar 

  • Yu RZ, Kim TW, Hong A et al (2007) Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100. Drug Metab Dispos 35:460–468

    Article  PubMed  CAS  Google Scholar 

  • Yu RZ, Geary RS, Flaim JD et al (2009) Lack of pharmacokinetic interaction of mipomersen sodium (ISIS 301012), a 2′-O-methoxyethyl modified antisense oligonucleotide targeting apolipoprotein B-100 messenger RNA, with simvastatin and ezetimibe. Clin Pharmacokinet 48:39–50

    Article  PubMed  CAS  Google Scholar 

  • Zellweger T, Miyake H, Cooper S (2001) Antitumor activity of antisense clusterin oligonucleotides is improved in vitro and in vivo by incorporation of 2′-O-(2-methoxy)ethyl chemistry. J Pharmacol Exp Ther 298:934–940

    PubMed  CAS  Google Scholar 

  • Zellweger T, Chi K, Miyake H et al (2002) Enhanced radiation sensitivity in prostate cancer by inhibition of the cell survival protein clusterin. Clin Cancer Res 8:3276–3284

    PubMed  CAS  Google Scholar 

  • Zhang Q, Zhou W, Kundu S et al (2006) The leader sequence triggers and enhances several functions of clusterin and is instrumental in the progression of human prostate cancer in vivo and in vitro. BJU Int 98:452–460

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, Medical Faculty, Dresden University of Technology, Fetscherstraße 74, 01307, Dresden, Germany

    Doreen Kunze, Kai Kraemer & Susanne Fuessel

Authors
  1. Doreen Kunze
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai Kraemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susanne Fuessel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Doreen Kunze .

Editor information

Editors and Affiliations

  1. Inst. Chemie und Biochemie, FU Berlin, Thielallee 63, Berlin, 14195, Germany

    Volker A. Erdmann

  2. Inst. Bioorganic Chemistry, PAN Poznan, ul. Z. Noskowskiego 12/14, Poznan, 61-704, Poland

    Jan Barciszewski

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kunze, D., Kraemer, K., Fuessel, S. (2010). Antisense Oligonucleotides: Insights from Preclinical Studies and Clinical Trials. In: Erdmann, V., Barciszewski, J. (eds) RNA Technologies and Their Applications. RNA Technologies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-12168-5_13

Download citation

Publish with us

Policies and ethics

Search

Navigation