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Published online 3 February 2004

Nucleic Acids Research, 2004, Vol. 32, No. 2 828-833
© 2004 Oxford University Press

2'-O-[2-[(N,N-dimethylamino)oxy]ethyl]-modified oligonucleotides inhibit expression of mRNA in vitro and in vivo

Thazha P. Prakash, Joseph F. Johnston, Mark J. Graham, Thomas P. Condon and Muthiah Manoharan*

Isis Pharmaceuticals Inc., 2292 Faraday Avenue, Carlsbad, CA 92008, USA

*To whom correspondence should be addressed. Tel: +1 617 252 0700 ext. 2319; Fax: +1 617 252 011; Email: mmanoharan{at}alnylam.com
Present address:
M.Manoharan, Alnylam Pharmaceuticals, 790 Memorial Drive, Suite 202, Cambridge, MA 02139, USA.

Synthesis and antisense activity of oligonucleotides modified with 2'-O-[2-[(N,N-dimethylamino)oxy] ethyl] (2'-O-DMAOE) are described. The 2'-O-DMAOE-modified oligonucleotides showed superior metabolic stability in mice. The phosphorothioate oligonucleotide ‘gapmers’, with 2'-O-DMAOE- modified nucleoside residues at the ends and 2'-deoxy nucleosides residues in the central region, showed dose-dependent inhibition of mRNA expression in cell culture for two targets. ‘Gapmer’ oligonucleotides have one or two 2'-O-modified regions and a 2'-deoxyoligonucleotide phosphorothioate region that allows RNase H digestion of target mRNA. To determine the in vivo potency and efficacy, BalbC mice were treated with 2'-O-DMAOE gapmers and a dose-dependent reduction in the targeted C-raf mRNA expression was observed. Oligonucleotides with 2'-O-DMAOE modifications throughout the sequences reduced the intercellular adhesion molecule-1 (ICAM-1) protein expression very efficiently in HUVEC cells with an IC50 of 1.8 nM. The inhibition of ICAM-1 protein expression by these uniformly modified 2'-O-DMAOE oligonucleotides may be due to selective interference with the formation of the translational initiation complex. These results demonstrate that 2'-O-DMAOE- modified oligonucleotides are useful for antisense-based therapeutics when either RNase H-dependent or RNase H-independent target reduction mechanisms are employed.


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