Effective silencing of ENaC by siRNA delivered with epithelial-targeted nanocomplexes in human cystic fibrosis cells and in mouse lung
Open accessAbstract
Introduction Loss of the cystic fibrosis transmembrane conductance regulator in cystic fibrosis (CF) leads to hyperabsorption of sodium and fluid from the airway due to upregulation of the epithelial sodium channel (ENaC). Thickened mucus and depleted airway surface liquid (ASL) then lead to impaired mucociliary clearance. ENaC regulation is thus a promising target for CF therapy. Our aim was to develop siRNA nanocomplexes that mediate effective silencing of airway epithelial ENaC in vitro and in vivo with functional correction of epithelial ion and fluid transport. Methods We investigated translocation of nanocomplexes through mucus and their transfection efficiency in primary CF epithelial cells grown at air–liquid interface (ALI).Short interfering RNA (SiRNA)-mediated silencing was examined by quantitative RT-PCR and western analysis of ENaC. Transepithelial potential (Vt), short circuit current (Isc), ASL depth and ciliary beat frequency (CBF) were measured for functional analysis. Inflammation was analysed by histological analysis of normal mouse lung tissue sections. Results Nanocomplexes translocated more rapidly than siRNA alone through mucus. Transfections of primary CF epithelial cells with nanocomplexes targeting αENaC siRNA, reduced αENaC and βENaC mRNA by 30%. Transfections reduced Vt, the amiloride-sensitive Isc and mucus protein concentration while increasing ASL depth and CBF to normal levels. A single dose of siRNA in mouse lung silenced ENaC by approximately 30%, which persisted for at least 7 days. Three doses of siRNA increased silencing to approximately 50%. Conclusion Nanoparticle-mediated delivery of ENaCsiRNA to ALI cultures corrected aspects of the mucociliary defect in human CF cells and offers effective delivery and silencing in vivo.
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LPR nanocomplexes facilitated translocation of siRNA through mucus, mediated efficient ENaCsiRNA transfections in primary CF epithelial cells, and reduced 30% of αENaC and βENaC mRNA.
“Results showed that the established LPR nanocomplexes facilitated the translocation of siRNA through mucus, mediated efficient ENaCsiRNA transfections in primary CF epithelial cells, and reduced 30% of the αENaC and βENaC mRNA.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [96]
Manunta et al. reported an ENaCsiRNA nanocomplex that induced effective in vitro and in vivo silencing of airway ENaC.
“In 2017, Manunta et al. reported the development of an ENaCsiRNA nanocomplex that induced effective in vitro and in vivo silencing of airway ENaC.[95, 96]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [96]
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RNA delivery biomaterials for the treatment of genetic and rare diseases
Zhao, W., Hou, X., Vick, O. G., & Dong, Y. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119291 · Cited by 82 · see citing works
- Authors
- Tagalakis, A. D., Munye, M. M., Ivanova, R., Chen, H., Smith, C. M., Aldossary, A. M., Rosa, L. Z., Moulding, D., Barnes, J. L., Kafetzis, K. N., Jones, S. A., Baines, D. L., Moss, G. W. J., O’Callaghan, C., McAnulty, R. J., & Hart, S. L.
- Affiliations
- University College London (GB)
- King's College London (GB)
- St George's, University of London (GB)
- Corresponding author
- Tagalakis, Aristides D
- ORCID
- Venue
- Thorax
- Publisher
- BMJ
- Published
- 2018-05-10
- Volume
- 73
- Issue
- 9
- Pages
- 847-856
- ISSN
- 0040-6376 (ISSN-L)
- 1468-3296
- PMC
- PMC6109249
- OpenAlex
- W2800938802
- Cited by
- 61
- References
- 65
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 11 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 9
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Thorax (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (acceptedVersion, cc-by)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Edge Hill University Research Information Repository (Edge Hill University) (submittedVersion, cc-by-nc-nd)
- Edge Hill University (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Cystic Fibrosis Trust
- Action Medical Research
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Keywords
- cystic fibrosis, epithelial sodium channel, siRNA delivery, nanocomplexes, airway epithelial cells, air-liquid interface, airway surface liquid, mucociliary clearance, transepithelial potential, short-circuit current, ciliary beat frequency, lung inflammation, CFTR
- MeSH terms
- Animals, Cystic Fibrosis, Disease Models, Animal, Humans, Transfection, Cell Culture Techniques, Gene Silencing, RNA, Small Interfering, Mice, Epithelial Sodium Channels, Nanoparticles
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