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  • Review Article
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Therapeutic Applications of Oligonucleotides

Bio/Technology volume 10, pages 882–886 (1992)Cite this article

Abstract

This review focuses strictly on the pharmacodynamic considerations of the use of oligonucleotides designed to interact with nucleic acids as therapeutics. The objectives are to place oligonucleotide therapeutics in the context of modern drug discovery and development and to summarize recent progress.

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References

  1. Zamecnik, P.C. and Stephenson, M.L. 1978. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleolide. Proc. Natl. Acad. Sci. USA 75: 280–284.

    Article  CAS  Google Scholar 

  2. Mizumoto, K. and Kaziro, Y. 1987. Messenger RNA capping enzymes from eukaryotic cells, p. 1–28. In: Progress in Nucleic Acid. Res. and Mol. Biol. Vol. 34. Editor? Academic Press, NY.

    Google Scholar 

  3. Ross, J. 1988. Messenger RNA turnover in eukaryotic cells. Mol. Biol. Med. 5: 1–xxx.

    CAS  PubMed  Google Scholar 

  4. Friedman, D.I., Imperiale, M.J. and Adhya, S.L. 1987. RNA 3′ end formation in the control of gene expression. Ann. Rev. Genet. 21: 453–488.

    Article  CAS  Google Scholar 

  5. Manley, J.L. 1988. Polyadenylation of mRNA precursors. Biochinlica et Biophysica Acta 950: 1–12.

    Article  CAS  Google Scholar 

  6. Padgett, R.A., Grabowski, P.J., Konarska, M.M., Seiler, S. and Sharp, P.A. 1986. Splicing of messenger RNA precursors. Ann. Rev. Biochem. 55: 1119–1150.

    Article  CAS  Google Scholar 

  7. Green, M.R. 1986. Pre-mRNA splicing. Ann. Rev. Genet. 20: 671–708.

    Article  CAS  Google Scholar 

  8. Freier, S.M., Kierzek, R., Jaeger, J.A., Sugimoto, N., Caruthers, M.H. and Neilson, T. 1986. Improved free-energy parameters for predictions of RNA duplex stability. Proc. Natl. Acad. Sci. USA 83: 9373–9377.

    Article  CAS  Google Scholar 

  9. Breslauer, K.J., Frank, R., Blocker, H. and Marky, L.A. 1986. Predicting DNA duplex stability from base sequence. Proc. Natl. Acad. Sci. USA 83: 3746–3750.

    Article  CAS  Google Scholar 

  10. Cook, P.D. 1991. Medicinal chemistry of antisense oligonucleotides—future opportunities. Anti-Cancer Drug Design 6: 585–607.

    CAS  PubMed  Google Scholar 

  11. Nielsen, P.K., Egholm, M., Berg, R.H. and Buchardt, O. 1991. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 254: 1497–1500.

    Article  CAS  Google Scholar 

  12. Freier, S.M., Lima, W.F., Sanghvi, Y.S., Vickers, T., Zounes, M., Cook, P.D. and Ecker, D.J. 1991. Thermodynamics of antisense oligonucleotide hybridization, p. 95–107. Gene Regulation Biology of Antisense RNA and DNA. Ivant, J. and Krickson, R. (Eds.). Raven Press, NY.

    Google Scholar 

  13. Cazenave, C. and Helene, C. 1991. Antisense oligonucieotides. In: Anti-sense Nucleic Acids and Proteins. Fundamentals and Applications. Mol, J. N. M. and van der Krol A. R. (Eds.). Marcel Dekker, Inc., NY.

    Google Scholar 

  14. Puglisi, J.D., Wyatt, J.R. and Tinoco, I. Jr. 1990. Conformation of an RNA Pseudoknot. J. Mol. Biol. 214: 437–453.

    Article  CAS  Google Scholar 

  15. Uhlmann, E. and Peyman, A. 1990. Antisense oligonucleotides: A new therapeutic principle. Chemical Reviews 90: 543–584.

    Article  CAS  Google Scholar 

  16. Cohen, J.S., Ed. 1989. Oligodeoxynucleotides. Anlisense Inhibitors of Gene Expression. CRC Press, Inc., Boca Raton, FL.

    Google Scholar 

  17. Mol, J.N.M. and van der Krol, A.R. (Eds.) 1991. Antisense Nucleic Acids and Proteins. Fundamentals and Applications. Marcel Dekker, Inc., NY

  18. Kulka, M., Smith, C., Aurelian, L., Fishelevich, R., Meade, K., Miller, P. and Ts'o, P. 1989. Site specificity of the inhibitory effects of oligo (nucleoside methylphosphonates) complementary to the acceptor splice junction of herpes simplex virus type 1 immediately early mRNA. Proc. Natl. Acad. Sci. USA 86: 6868–6872.

    Article  CAS  Google Scholar 

  19. Vlassov, V.V. 1989. Inhibition of tick-borne viral encephalitis expression using covalently linked oligonucleotide analogs. Meeting on: Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression: Therapeutic Implications, June 18–21, 1989. Rockville, MD. (Abstract)

  20. Brandt, C.R., Coakley, L.M., Grau, D.R., Draper, K.G. and Mirabelli, C.K. 1992. Treatment of HSV-1 induced ocular disease with a phos-phorothioate oligonucleotide, ISIS 1082. Antimicrobial Agents and Chemotherapy. Submitted.

  21. Zamecnik, P.C., Goodchild, J., Taguchi, Y. and Sarin, P.S. 1986. Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA. Proc. Natl. Acad. Sci. USA 83: 4143–4146.

    Article  CAS  Google Scholar 

  22. Matsukura, M., Shinozuka, K., Zon, G., Mitsuya, H., Reitz, M., Cohen, J.S. and Broder, S. 1987. Phosphorothioate analogs of oligodeoxynucleotides: Inhibitors of replication and cytopathic effects of human immunodeficiency virus. Proc. Natl. Acad. Sci. USA 84: 7706–7710.

    Article  CAS  Google Scholar 

  23. Stec, W.J., Zon, G., Egan, W. and Stec, B. 1984. Automated solid-phase synthesis, separation and stereochemistry of phosphorothioate analogues of Oligodeoxynucleotides. J. Am. Cheni. Soc. 106: 6077–6079.

    Article  CAS  Google Scholar 

  24. Agrawal, S., Goodchild, J., Civeira, M.P., Thornton, A.T., Sarin, P.M. and Zamecnik, P.C. 1988. Oligodeoxynucleoside phosphoramidites and phosphorothioates as inhibitors of human immunodeficiency virus. Proc. Natl. Acad. Sci. USA 85: 7079–7083.

    Article  CAS  Google Scholar 

  25. Vickers, T., Baker, B.E., Cook, P.D., Zounes, M., Buckheit, R.W. Jr., Germany, J. and Ecker, D.J. 1991. Inhibition of HIV-LTR gene expression by oligonucleotides targeted to the TAR element. Nucl. Acids Res. 19: 3359–3368.

    Article  CAS  Google Scholar 

  26. Smith, C.C., Aurelian, L., Reddy, M.P., Miller, P.S. and Ts'o, P.O.P. 1986. Antiviral effect of an oligo (nucleoside methylphosphonate) complementary to the splice junction of herpes simplex virus type I immediate early pre-mRNAs 4 and 5. Proc. Natl. Acad. Sci. USA 83: 2787–2791.

    Article  CAS  Google Scholar 

  27. Gao, W., Stein, C.A., Cohen, J.S., Dutschman, G.E. and Cheng, C.-Y. 1989. Effect of phosphorothioate homo-ohgodeoxy-nucleotides on herpes simplex virus type 2-induced DNA polymerase. J. Biol. Chem. 264: 11521–11526.

    CAS  PubMed  Google Scholar 

  28. Cazenave, C., Cherrier, M., Nguyen, T.T. and Helene, C. 1987. Rate of degradation of alpha and beta-oligodeoxynucleotides in Xenopus oocytes: implications for anti-messenger strategies. Nucl. Acids Res. 15: 10507–10521.

    Article  CAS  Google Scholar 

  29. Draper, K.G., Driver, V.B., Hoke, G., Gonzalez, C. and Anderson, K.P. 1992. Inhibition of herpes simplex virus replication using phosphorothioate oligonucleotides complementary to viral mRNA. Antimicrobial Agents and Chemotherapy. Submitted.

    Google Scholar 

  30. Agris, C.H., Blake, K.R., Miller, P.S., Reddy, M.P. and Ts'o, P.O.P. 1986. Inhibition of vesicular stomatitis virus protein synthesis and infection by sequence-specific oligodeoxyribonucleoside methylphosphonates. Bio chemistry 25: 6268–6275.

    CAS  Google Scholar 

  31. Shea, R.G., Marsters, J.C. and Bischofberger, N. 1990. Synthesis, hybridization properties and antiviral activity of lipid-oligodeoxynucleotide conjugates. Nucl. Acids Res. 18: 3777–3783.

    Article  CAS  Google Scholar 

  32. Lemaitre, M., Bayard, B. and Lebleu, B. 1987. Specific antiviral activity of a poly (L-lysine)-conjugated oligodeoxyribonucleotide sequence complementary to vesicular stomatitis virus N protein mRNA initiation site. Biochemistry. 84: 648–652.

    CAS  Google Scholar 

  33. Zerial, A., Thuong, N.T. and Helene, C. 1987. Selective inhibition of the cytopathic effect of type A influenza viruses by Oligodeoxynucleotides covalently linked to an intercalating agent. Nucl. Acids Res. 15: 9909–9919.

    Article  CAS  Google Scholar 

  34. Miller, P.S., Agris, C.H., Aurelian, L., Blake, K.R., Murakami, A., Reddy, M.P., Spitz, S.A. and Ts'o, P.O.P. 1985. Control of ribonucleic acid function by oligonucleoside methylphosphonates. Biochimie 67: 769–776.

    Article  CAS  Google Scholar 

  35. Goodarzi, G., Gross, S.C., Tewari, A. and Watabe, K. 1990. Antisense oligodeoxyribonucleotides inhibit the expression of the gene for hepatitis B virus surface antigen. J. Gen. Virol. 71: 3021–3025.

    Article  CAS  Google Scholar 

  36. Cowsert, L.M., Fox, M.C. and Zon, G. 1992. Gene expression by phos phorothioate oligonuleotides complementary to F2 mRNA. Nucl. Acids Res. Submitted.

  37. Heikkila, R., Schwab, G., Wickstrom, E., Loke, S.L., Pluznik, D.H., Watt, R. and Neckers, I.M. 1987. A c-myc antisense oligonucleotide inhibits entry into S phase but not progress from G0 to Gl. Nature 328: 445–449.

    Article  CAS  Google Scholar 

  38. Wickstrom, E.L., Bacon, T.A., Gonzalez, A.L.G.H., Lyman, G.H. and Wickstrom, E. 1989. Anti-c-myc DNA increases differentiation and decreases colony formation by HL-60 cells. In Vitro. Cell Develop. Biol. 25: 297–302.

    Article  CAS  Google Scholar 

  39. McManaway, M.K., Neckers, L.M., Loke, S.L., Al-Nasser, A.A., Redner, R.L., Shiramizu, B.T., Goldschmidts, W.L., Huber, B.K., Bhatia, K. and Magrath, I.T. 1996. Tumour-specific inhibition of lymphoma growth by an antisense oligodeoxynucleotide. Lancet 335: 808–811.

    Article  Google Scholar 

  40. Gewirtz, A.M., Anfossi, G., Venturelli, D., Valpreda, S. Sims, R. and Calabretta, B. 1988. A c-myb antisense oligodeoxynucleoside inhibits normal human hematopoiesis in vitro. Science 242: 1303–1306

    Article  CAS  Google Scholar 

  41. Reed, J.C., Guddy, M., Haldar, S., Croce, C., Nowell, P., Makover, D. and Bradley, K. 1990. BGL2-mediated tumorigenicity of a human T-Iyrnphoid cell line: synergy with myc and inhibition by BCL2 antisense. Proc. Natl. Acad. Sci. USA 87: 3660–3664.

    Article  CAS  Google Scholar 

  42. Tidd, D.M. Hawley, P., Warenius, H.M. and Gibson, I. 1988. Evaluation of N-ras oncogene antisense, sense and nonsense sequence methylphosphonate oligonucleotide analogues. Anti-Cancer Drug Design 3: 117–127.

    CAS  PubMed  Google Scholar 

  43. Jaroszewski, J.W., Kaplan, O., Syi, J.L., Sehested, M., Faustino, P. and Cohen, J.S. 1990. Concerning antisense inhibition of the multiple drug resistance gene. Cancer Comm. 2: 287–294.

    Article  CAS  Google Scholar 

  44. Jaskulski, D., DeRiel, J.K., Mercer, W.E., Calabretta, B. and Baserga, R. 1989. Inhibition of cellular proliferation by antisense oligodeoxynucleotides to PCNA cyclin. Science 240: 1544–1546.

    Article  Google Scholar 

  45. Sburlati, A.R., Manrow, R.E. and Berger, S.L. 1991. Prothymosin-α antisense oligomers inhibit myeloma cell division. Proc. Natl. Acad. Sci. USA 88: 253–257.

    Article  CAS  Google Scholar 

  46. Zheng, H., Sahai, B.M., Kilgannon, P., Fotedar, A. and Green, D.R. 1989. Specific inhibition of cell-surface T-cell receptor expression by antisense oligodeoxynucleotides and its effect on the production of an antigen-specific regulatory T-cell factor. Proc. Natl. Acad. Sci. USA 86: 3758–3762.

    Article  CAS  Google Scholar 

  47. Birchenall Roberts, M.C., Falk, L.A., Ferrer, C. and Ruscetti, F.W. 1989. A CSF-1 antisense oligodeoxynucleotide inhibits proliferation of immortalized murine monocytes establishment of autocrine regulation. J. Cell. Biochem. Supple. 13 (Part C): 18.

  48. Yeoman, L.C., Daniels, Y.J. and Lynch, M.J. 1989. Inhibition of colon tumor cell growth by direct addition of anti-EGF receptor oligodeoxyribonucleotides. Meeting on: Oligodeoxynucleotides as Antisense Inhibitors of Gene Fxpression: Therapeutic Implications, June 18–21. 1989, Rockville, MD. (Abstract)

  49. Morrison, R.S. 1991. Suppression of basic fibroblast growth factor expression by antisense oligodeoxynucleolides inhibits the growth of transformed human astrocytes. J. Biol. Chem. 266: 728–734.

    CAS  PubMed  Google Scholar 

  50. Blake, K.R., Murakami, A. and Miller, P.S. 1985. Inhibition of rabbit globin mRNA translation by sequence specific oligodeoxyribonucleotides. Biochemistry 24: 6132–6138.

    Article  CAS  Google Scholar 

  51. Caceres, A. and Kosik, K.S. 1990. Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature 343: 461–463.

    Article  CAS  Google Scholar 

  52. Tortora, G., Clair, T. and Cho-Chung, Y.S. 1990. An antisense oligodeoxynucleotide targeted against the type IIβ; regulatory subunit mRNA of protein kinase inhibits cAMP-induced differentiation in HL.-60 leukemia cells without affecting phorbol ester effects. Proc. Natl. Acad. Sci. USA 87: 705–708.

    Article  CAS  Google Scholar 

  53. Bories, D., Raynal, M-C., Solomon, D.H., Darzynkiewkz, Z. and Cayre, Y.K. 1989. Down-regulation of serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells. Cell 59: 959–968.

    Article  CAS  Google Scholar 

  54. Clark, M.A., Ozgur, L.F., Conway, T.M., Dispoto, J., Crooke, S.T. and Bomalaski, J.S. 1991. Cloning of a phospholipase A2-activating protein. Proc. Natl. Acad. Sci. USA 88: 5418–5422.

    Article  CAS  Google Scholar 

  55. Maier, J.A.M., Voulalas, P., Roeder, D. and Maciag, T. 1990. Fxtension of the life-span of human endothelial cells by an interleukin-lα antisense oligomer. Science 249: 1570–1574.

    Article  CAS  Google Scholar 

  56. Harel-Bellan, A., Durum, S., Muegge, K., Abbas, A.K. and Farrar, W.L. 1988. Specific inhibition of lymphokint biosynthesis and autocrine growth using antisense oligonucleotides in Th1 and Th2 helper T cell clones. J. Fxp. Med. 168: 2309–2318.

    Article  CAS  Google Scholar 

  57. Manson, J., Brown, T. and Duff, G. 1990. Modulation of interleukin 1β gene expression using antisense phosphorothioate oligormcletides. Lymphokine Res. 9: 35–42.

    CAS  PubMed  Google Scholar 

  58. Florini, J.R. and Ewton, D.Z. 1990. Highly specific inhibition of IGF-I-slimulated differentiation by an antisense oligodeoxyribonucleotide to myogenin mRNA. J. Biol Chem. 265: 13435–13437.

    CAS  PubMed  Google Scholar 

  59. Acha-Orbea, H., Scarpellino, I., Hertig, S., Dupuis, M. and Tschopp, J. 1990. Inhibition of lymphocyte mediated cytotoxicity by perforin anti-sense oligonucleotides. EMBO J. 9: 3815–3819.

    Article  CAS  Google Scholar 

  60. Marcus-Sekura, C.J., Woerner, A.M., Shinozuka, K., Zon, G. and Quinnan, G.V., Jr. 1987. Comparative inhibition of chloramphenicol acetyltransferase gene expression by antisense oligonucleotide analogues having alkyl phosphotriester, methylphosphonate and phosphorothioate linkages. Nucl. Acids Res. 15: 5749–5763.

    Article  CAS  Google Scholar 

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    Stanley T. Crooke

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Crooke, S. Therapeutic Applications of Oligonucleotides. Nat Biotechnol 10, 882–886 (1992). https://doi.org/10.1038/nbt0892-882

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