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- Title
Systemically delivered antisense oligomers upregulate gene expression in mouse tissues.
- Authors
Sazani, Peter; Gemignani, Federica; Kang, Shin-Hong; Maier, Martin A.; Manoharan, Muthiah; Persmark, Magnus; Bortner, Donna; Kole, Ryszard
- Abstract
Systemically injected 2'-O-methoxyethyl (2'-O-MOE)-phosphorothioate and PNA-4K oligomers (peptide nucleic acid with four lysines linked at the C terminus) exhibited sequence-specific antisense activity in a number of mouse organs. Morpholino oligomers were less effective, whereas PNA oligomers with only one lysine (PNA-1K) were completely inactive. The latter result indicates that the four-lysine tail is essential for the antisense activity of PNA oligomers in vivo. These results were obtained in a transgenic mouse model designed as a positive readout test for activity, delivery, and distribution of antisense oligomers. In this model, the expressed gene (EGFP-654) encoding enhanced green fluorescence protein (EGFP) is interrupted by an aberrantly spliced mutated intron of the human β-globin gene. Aberrant splicing of this intron prevented expression of EGFP-654 in all tissues, whereas in tissues and organs that took up a splice site-targeted antisense oligomer, correct splicing was restored and EGFP-654 expression upregulated. The sequence-specific ability of PNA-4K and the 2'-O-MOE oligomers to upregulate EGFP-654 provides strong evidence that systemically delivered, chemically modified oligonucleotides affect gene expression by sequence-specific true antisense activity, validating their application as potential therapeutics.
- Subjects
GENE expression; ANTISENSE nucleic acids; OLIGOMERS
- Publication
Nature Biotechnology, 2002, Vol 20, Issue 12, p1228
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt759