Systemically delivered antisense oligomers upregulate gene expression in mouse tissues View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2002-12

AUTHORS

Peter Sazani, Federica Gemignani, Shin-Hong Kang, Martin A. Maier, Muthiah Manoharan, Magnus Persmark, Donna Bortner, Ryszard Kole

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 beta-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. More... »

PAGES

1228

Journal

TITLE

Nature Biotechnology

ISSUE

12

VOLUME

20

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nbt759

    DOI

    http://dx.doi.org/10.1038/nbt759

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1052496847

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/12426578


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