Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis

Abstract The inhibition of ENaC may have therapeutic potential in CF airways by reducing sodium hyperabsorption, restoring lung epithelial surface fluid levels, airway hydration and mucociliary function. The challenge has been to deliver siRNA to the lung with sufficient efficacy for a sustained the...

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Autores principales:	Maria D. I. Manunta, Aristides D. Tagalakis, Martin Attwood, Ahmad M. Aldossary, Josephine L. Barnes, Mustafa M. Munye, Alexander Weng, Robin J McAnulty, Stephen L. Hart
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e1dcd0da9f604c4c97453b6b34085cf2
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spelling	oai:doaj.org-article:e1dcd0da9f604c4c97453b6b34085cf22021-12-02T16:06:45ZDelivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis10.1038/s41598-017-00662-22045-2322https://doaj.org/article/e1dcd0da9f604c4c97453b6b34085cf22017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00662-2https://doaj.org/toc/2045-2322Abstract The inhibition of ENaC may have therapeutic potential in CF airways by reducing sodium hyperabsorption, restoring lung epithelial surface fluid levels, airway hydration and mucociliary function. The challenge has been to deliver siRNA to the lung with sufficient efficacy for a sustained therapeutic effect. We have developed a self-assembling nanocomplex formulation for siRNA delivery to the airways that consists of a liposome (DOTMA/DOPE; L), an epithelial targeting peptide (P) and siRNA (R). LPR formulations were assessed for their ability to silence expression of the transcript of the gene encoding the α-subunit of the sodium channel ENaC in cell lines and primary epithelial cells, in submerged cultures or grown in air-liquid interface conditions. LPRs, containing 50 nM or 100 nM siRNA, showed high levels of silencing, particularly in primary airway epithelial cells. When nebulised these nanocomplexes still retained their biophysical properties and transfection efficiencies. The silencing ability was determined at protein level by confocal microscopy and western blotting. In vivo data demonstrated that these nanoparticles had the ability to silence expression of the α-ENaC subunit gene. In conclusion, these findings show that LPRs can modulate the activity of ENaC and this approach might be promising as co-adjuvant therapy for cystic fibrosis.Maria D. I. ManuntaAristides D. TagalakisMartin AttwoodAhmad M. AldossaryJosephine L. BarnesMustafa M. MunyeAlexander WengRobin J McAnultyStephen L. HartNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maria D. I. Manunta Aristides D. Tagalakis Martin Attwood Ahmad M. Aldossary Josephine L. Barnes Mustafa M. Munye Alexander Weng Robin J McAnulty Stephen L. Hart Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis
description	Abstract The inhibition of ENaC may have therapeutic potential in CF airways by reducing sodium hyperabsorption, restoring lung epithelial surface fluid levels, airway hydration and mucociliary function. The challenge has been to deliver siRNA to the lung with sufficient efficacy for a sustained therapeutic effect. We have developed a self-assembling nanocomplex formulation for siRNA delivery to the airways that consists of a liposome (DOTMA/DOPE; L), an epithelial targeting peptide (P) and siRNA (R). LPR formulations were assessed for their ability to silence expression of the transcript of the gene encoding the α-subunit of the sodium channel ENaC in cell lines and primary epithelial cells, in submerged cultures or grown in air-liquid interface conditions. LPRs, containing 50 nM or 100 nM siRNA, showed high levels of silencing, particularly in primary airway epithelial cells. When nebulised these nanocomplexes still retained their biophysical properties and transfection efficiencies. The silencing ability was determined at protein level by confocal microscopy and western blotting. In vivo data demonstrated that these nanoparticles had the ability to silence expression of the α-ENaC subunit gene. In conclusion, these findings show that LPRs can modulate the activity of ENaC and this approach might be promising as co-adjuvant therapy for cystic fibrosis.
format	article
author	Maria D. I. Manunta Aristides D. Tagalakis Martin Attwood Ahmad M. Aldossary Josephine L. Barnes Mustafa M. Munye Alexander Weng Robin J McAnulty Stephen L. Hart
author_facet	Maria D. I. Manunta Aristides D. Tagalakis Martin Attwood Ahmad M. Aldossary Josephine L. Barnes Mustafa M. Munye Alexander Weng Robin J McAnulty Stephen L. Hart
author_sort	Maria D. I. Manunta
title	Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis
title_short	Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis
title_full	Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis
title_fullStr	Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis
title_full_unstemmed	Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis
title_sort	delivery of enac sirna to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e1dcd0da9f604c4c97453b6b34085cf2
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Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis

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