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Identification of small interfering RNA targeting Signal Transducer and Activator of Transcription 6: Characterisation and selection of candidates for pre-clinical development


Research Article

J RNAi Gene Silencing (2010), 6(2), 401-410

doi: jrgsxx

Published online: 25 August 2010

Full Text: (html | pdf ~254kb | refs)

Identification of small interfering RNA targeting Signal Transducer and Activator of Transcription 6: Characterisation and selection of candidates for pre-clinical development

Gareth D Healey †*, Shawn Zinnen †, Jennifer A Lockridge †¥, Ivan Richards †, Neil Evans † and William Walker †‡

† Allerna Therapeutics Ltd, Institute of Life Science, Swansea University, Swansea, SA2 8PP, UK

‡ School of Medicine, Institute of Life Science, Swansea University, Swansea, SA2 8PP, UK

¥ Lockridge Pharmaceutical Consulting, LLC, 9689 Otis Drive, Westminster, CO 80021, USA

*Correspondence toGareth Healey, Email: ghealey@allerna.com, Tel: +44 (0) 1792602903

Received: 28 June 2010, Revised: 18 August 2010, Accepted: 20 August 2010

© Copyright The Authors

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ABSTRACT

The interleukin (IL)-13 pathway and its associated transcription factor, signal transducer and activator of transcription 6 (STAT6), have been clearly implicated in the pathogenesis of bronchial asthma. We have developed a system to effectively screen the STAT6 gene for targeting with small interfering (si) RNA molecules. By incorporating an in silico and in vitro screening system we were able to identify fourteen siRNA molecules suitable for pre-clinical drug development. Furthermore, we were able to demonstrate that modification of certain siRNAs, designed to improve in vivo longevity, was possible without significant loss of target knockdown efficacy and that the siRNA produced by our selection process did not induce demonstrable interferon responses. These data suggest that several STAT6-targeting siRNA suitable for pre-clinical development are available for potential use in the treatment of asthma.

KEYWORDS: Asthma, STAT6, IL-13, siRNA, pre-clinical development

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