Second Generation of Antisense Oligonucleotides: From Nuclease Resistance to Biological Efficacy in Animals


  • Karl-Heinz Altmann
  • Nicholas M. Dean
  • Doriano Fabbro
  • Susan M. Freier
  • Thomas Geiger
  • Robert Häner
  • Dieter Hüsken
  • Pierre Martin
  • Brett P. Monia
  • Marcel Müller
  • François Natt
  • Paul Nicklin
  • Judy Phillips
  • Uwe Pieles
  • Henri Sasmor
  • Heinz E. Moser Central Research Laboratories, Ciba-Geigy Ltd., Postfach, CH-4002 Basel



From efforts to improve the biophysical properties of antisense oligonucleotides by incorporating backbone- or sugar-modified nucleoside analogs, 2'-O-methoxyethyl ribonucleosides 8b were identified as building blocks for a second generation of antisense oligonucleotides. Compounds containing these modifications were demonstrated to combine the benefit of a high binding affinity to the RNA complement with a large increase in nuclease resistance, allowing the use of regular phosphodiester linkages. Chimeric oligonucleotides with 2'-O-methoxyethyl ribonucleosides, 8b, in the wings and a central DNA-phosphorothioate window were shown to efficiently downregulate C-'raf' kinase and PKC-α messenger-RNA in tumor cell lines resulting in a profound inhibition of cell proliferation. The same compounds were able to effectively reduce the growth of tumors in animal models at low concentrations indicating the potential utility of these second generation antisense oligonucleotides for therapeutic applications.






Scientific Articles

How to Cite

K.-H. Altmann, N. M. Dean, D. Fabbro, S. M. Freier, T. Geiger, R. Häner, D. Hüsken, P. Martin, B. P. Monia, M. Müller, F. Natt, P. Nicklin, J. Phillips, U. Pieles, H. Sasmor, H. E. Moser, Chimia 1996, 50, 168, DOI: 10.2533/chimia.1996.168.