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Antisense oligonucleotides induced splice switching of FN1 transcript

Aung-Htut, M.T., Fletcher, S. and Wilton, S. (2015) Antisense oligonucleotides induced splice switching of FN1 transcript. The Journal of Gene Medicine, 17 (8 - 9). PO9.

Link to Published Version: https://doi.org/10.1002/jgm.2834
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Abstract

Fibronectin, encoded by FN gene, is a glycosylated protein found on cell surfaces, in extracellular matrix and plasma. It is involved in many events, including cell adhesion, migration, wound healing and blood coagulation. Alternative splicing of the FN1 transcript produces up to 20 transcript variants, which are tissue and developmentally dependent and also regulated by physiological and pathological conditions. It has been shown that the presence of a fibronectin isoform containing an extra domain A (EDA+‐FN), normally absent from the circulation, may be an indicator of chronic inflammation and also promotes ischemia/reperfusion brain injury through a TLR4‐dependent mechanism. We reduced the levels of the EDA+‐FN isoform using splice switching antisense oligonucleotides (AO). AOs, comprising 2'‐O‐methyl modified bases on a phosphorothioate backbone, were designed to exclude the EDA domain in exon 33 from the FN1 transcript. The ratio of EDA+‐FN to EDA‐‐FN spliceoforms was analysed 24 h after the fibroblasts were transfected with AOs as cationic lipoplexes. The most efficient AO targeting exon 33 was able to induce an approximately 70% reduction in EDA+‐FN transcript in treated cells. Splice switching AOs are emerging as powerful tools in therapeutic alternative splicing. The exon skipping AO identified in this study will be further investigated for therapeutic potential in pathological conditions caused by elevated level of the EDA+‐FN isoform.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
Publisher: Wiley
Copyright: © 2015 John Wiley & Sons, Ltd.
Other Information: Poster presentation given @ Ninth Australasian Gene and Cell Therapy Society Meeting, The University of Melbourne, Parkville, Victoria 29 April - 1 May 2015
URI: http://researchrepository.murdoch.edu.au/id/eprint/59498
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