Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma
Article first published online: 13 FEB 2013
© 2013 The Authors Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
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Journal of Cellular and Molecular Medicine
Volume 17, Issue 3, pages 356–364, March 2013
How to Cite
Healey, G. D., Evans, N., Hopkin, J. M., Davies, G. and Walker, W. (2013), Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma. Journal of Cellular and Molecular Medicine, 17: 356–364. doi: 10.1111/jcmm.12014
- Issue published online: 28 MAR 2013
- Article first published online: 13 FEB 2013
- Manuscript Accepted: 28 NOV 2012
- Manuscript Received: 30 MAY 2012
- nasal epithelium;
The development of siRNA-based asthma therapeutics is currently hampered by a paucity of relevant biomarkers and the need to ascertain tissue-specific gene targeting in the context of active disease. Epithelial STAT6 expression is fundamental to asthma pathogenesis in which inflammatory changes are found throughout the respiratory tract. Therefore, to improve preclinical evaluation, we tested the efficacy of STAT6-targeting siRNA within nasal epithelial cells (NEC's) obtained from asthmatic and non-asthmatic donors. STAT6 expression was invariant in both donor groups and amenable to suppression by siRNA treatment. In addition, STAT6 mRNA was also suppressible by apically delivered siRNA treatment in comparative differentiated nasal epithelial cell-line monolayer cultures. Analysis of donor NEC's showed consistent elevation in CCL26 (eotaxin-3) mRNA within the asthmatic group suggesting potential as a relevant biomarker. Furthermore, targeting of STAT6 with siRNA attenuated IL-13-driven CCL26 expression in these cells, pointing to the utility of this approach in preclinical testing. Finally, siRNA-mediated suppression of STAT6 was independent of donor disease phenotype or epithelial cell differentiation status, signifying therapeutic potential.