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Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma

Gareth D Healey, Neil Evans, Julian M Hopkin, Gwyneth Davies Orcid Logo, William Walker Orcid Logo

Journal of Cellular and Molecular Medicine, Volume: 17, Issue: 3, Pages: 356 - 364

Swansea University Authors: Gwyneth Davies Orcid Logo, William Walker Orcid Logo

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DOI (Published version): 10.1111/jcmm.12014

Abstract

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...

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Published in: Journal of Cellular and Molecular Medicine
ISSN: 15821838
Published: 2013
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URI: https://cronfa.swan.ac.uk/Record/cronfa13398
first_indexed 2013-07-23T12:10:08Z
last_indexed 2019-07-01T19:17:45Z
id cronfa13398
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spelling 2019-07-01T15:05:40.1899473 v2 13398 2012-11-30 Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma 92d69cf8519a334ced3f55142c811d95 0000-0003-1218-1008 Gwyneth Davies Gwyneth Davies true false 1f736d4178747b6082940868d069894f 0000-0002-1940-5329 William Walker William Walker true false 2012-11-30 MEDS 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-targetting 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 of 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. Journal Article Journal of Cellular and Molecular Medicine 17 3 356 364 15821838 Asthma, biomarker, CCL26, nasal epithelium, preclinical, siRNA, STAT6 1 3 2013 2013-03-01 10.1111/jcmm.12014 In press, accepted 28/11/12 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2019-07-01T15:05:40.1899473 2012-11-30T09:35:11.5600534 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Gareth D Healey 1 Neil Evans 2 Julian M Hopkin 3 Gwyneth Davies 0000-0003-1218-1008 4 William Walker 0000-0002-1940-5329 5
title Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma
spellingShingle Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma
Gwyneth Davies
William Walker
title_short Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma
title_full Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma
title_fullStr Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma
title_full_unstemmed Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma
title_sort Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma
author_id_str_mv 92d69cf8519a334ced3f55142c811d95
1f736d4178747b6082940868d069894f
author_id_fullname_str_mv 92d69cf8519a334ced3f55142c811d95_***_Gwyneth Davies
1f736d4178747b6082940868d069894f_***_William Walker
author Gwyneth Davies
William Walker
author2 Gareth D Healey
Neil Evans
Julian M Hopkin
Gwyneth Davies
William Walker
format Journal article
container_title Journal of Cellular and Molecular Medicine
container_volume 17
container_issue 3
container_start_page 356
publishDate 2013
institution Swansea University
issn 15821838
doi_str_mv 10.1111/jcmm.12014
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
active_str 0
description 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-targetting 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 of 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.
published_date 2013-03-01T18:27:27Z
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score 11.048042

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