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J Venom Res
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Aptamers
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Aptamers 2019
03-04 April 2019, Oxford
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In vivo knock-down of multidrug resistance transporters ABCC1 and ABCC2 by AAV-delivered shRNAs and by artificial miRNAs


Research Article

J RNAi Gene Silencing (2011), 7, 434-442

doi: jrgsxx

Published online: 17 June 2011

Full Text: (pdf ~325kb)

In vivo knock-down of multidrug resistance transporters ABCC1 and ABCC2 by AAV-delivered shRNAs and by artificial miRNAs

Florie Borel †‡, Richard van Logtenstein †, Annemart Koornneef †, Piotr Maczuga †¥, Tita Ritsema †, Harald Petry †, Sander JH van Deventer †¥, Peter LM Jansen ‡, Pavlina Konstantinova †*

† Department of Research and Development, Amsterdam Molecular Therapeutics, Amsterdam, The Netherlands

‡ Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

¥ Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands

*Correspondence toPavlina Konstantinova, Email: p.konstantinova@amtbiopharma.com, Tel: +31 205662214. Fax: +31 205669272

Received: 05 May 2011, Revised: 03 June 2011, Accepted: 06 June 2011

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ABSTRACT

ABC transporters export clinically-relevant drugs and their over-expression causes multidrug resistance. In order to knock-down ABC transporters, ABCC1 and ABCC2, 13 shRNAs were developed. Four shRNA candidates were tested in vivo using self-complementary adeno-associated virus serotype 8. A strong, specific knock-down of Abbc2 was observed in mice liver, but at the cost of toxicity caused by oversaturation of the RNAi machinery due to high shRNA expression. Subsequent generation of artificial miRNAs showed better efficacy profile. These results demonstrate the feasibility of knocking down Abbc2 via AAV-delivered shRNAs to the liver, and encourage the use of miRNA in further therapeutics development.

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