Inhibition of IL-6 in mice by anti-NF-kappaB oligodeoxyribonucleotide N3'-->oligodeoxyribonnucleotide N3' --> P5' phosphoramidates.
Oligonucleotide N3'->P5' Phosphoramidates (PN) may confer advantages over unmodified phosphodiester compounds for therapeutic applications (1). Previous in vitro data demonstrated that PN Oligodeoxynucleotides (ODNs) possess several advantageous features, including RNase H-independence, an improved resistance to nuclease degradation, decreased protein binding, and high affinity sequence-specific binding to complementary RNAs (1, 2). Consequently, we undertook a study to investigate the effects of PN antisense (AS) oligos targeted against the p65 subunit of the Nuclear Factor Kappa beta (NF-kappaB) transcription factor in vivo, in mice. The ability of the antisense molecules to inhibit IL-6 elevation induced by lipopolysaccharide (LPS) in mice, was studied. A 16 mer uniformly modified PN and a chimeric phosphoramidate-phosphodiester oligodeoxynucleotide complementary to the region surrounding the starting codon, (PN-PO-PN) of the NK-kappaB p65 subunit mRNA, both caused a sequence specific reduction of the serum IL-6 level in mice. A scrambled oligodeoxynucleotide showed much lower IL-6 inhibition in mice. These results show that the p65 PN-AS can modulate expression of IL-6 in mice without uptake enhancers and therefore may be a useful prototype for RNAse-H independent therapeutic agents.
Wang
L
L
Medical Biology Institute, Hayward, California 94545, USA.
Gryaznov
S
S
Nerenberg
M
M
D000577:Amides / Q000037:antagonists & inhibitors*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
D000577:Amides; D015850:Interleukin-6; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D010756:Phosphoric Acids; D000093242:Interleukin-6 Inhibitors; C011067:phosphoramidic acid