title: Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA-based therapeutics for asthma.
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 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.
authors: College of Medicine, Institute of Life Science, Swansea University, Swansea, UK. g.d.healey@swansea.ac.uk
authors: Gareth D
authors: GD
authors: Healey
authors: Neil
authors: N
authors: Evans
authors: Julian M
authors: JM
authors: Hopkin
authors: Gwyneth
authors: G
authors: Davies
authors: William
authors: W
authors: Walker
mesh_terms: D000328:Adult; D001249:Asthma / Q000235:genetics / Q000628:therapy*; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human
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