Allergy 2013 May (2)-7

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

J Cell Mol Med. 2013 Mar;17(3):356-64

Healey GD, Evans N, Hopkin JM, Davies G, Walker W.

College of Medicine, Institute of Life Science, Swansea University, Swansea, UK.


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. © 2013 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

PMID: 23402658


Additional text:

Asthma is a complex inflammatory disease of the airway which affects an estimated 300 million people worldwide. Over the past decade, knowledge of the molecular mechanisms involved in asthma pathogenesis has improved significantly with due emphasis on the role of epithelium in the chronic inflammatory and remodelling bronchial disorder. This has provided a framework for the development of new therapeutic strategies with the potential for fewer adverse side-effects.

Our work focuses on the use of a naturally occurring cellular control mechanism called RNA interference, which is a highly specific way of disrupting protein production from particular genes and therefore has important potential for delivering precisely targeted therapeutics. We have developed RNA interference based therapeutics targeting a key protein involved in asthma pathogenesis (STAT6) and our recent work describes efforts to develop these further. Within this publication we demonstrate that cells isolated from the nasal passages of asthma patients show a similar disease phenotype to cells isolated from the bronchial airways. We also show that these cells are amenable to treatment with our therapeutics. Whilst there are still major challenges in the use of RNA interference based therapeutics for respiratory diseases, particularly in relation to delivery technologies, our work suggests that using the nasal passages as an initial surrogate target may provide a useful tool to aid development of therapeutics for bronchial asthma.

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