Antisense oligonucleotides for therapy of cystic fibrosis. Inhibition of sodium absorption mediated by ENaC in nasal epithelial cells

• Published in: HNO 2009-11, Vol.57 (11), p.1106-1112
• Main Authors: Sobczak, K, Bangel-Ruland, N, Semmler, J, Lindemann, H, Heermann, R, Weber, W-M
• Format: Article
• Language: ger
• Subjects: Amiloride - pharmacology; Blotting, Western; Cells, Cultured; Cystic Fibrosis - drug therapy; Cystic Fibrosis - physiopathology; Epithelial Sodium Channel Blockers; Humans; Microscopy, Fluorescence; Nasal Mucosa - drug effects; Oligoribonucleotides, Antisense - genetics; Oligoribonucleotides, Antisense - pharmacology; Oligoribonucleotides, Antisense - therapeutic use; Sodium - metabolism; Sodium Channel Blockers - pharmacology; Transfection
• ISSN: 1433-0458
• DOI: 10.1007/s00106-009-1957-5

The genetic disease cystic fibrosis (CF) is characterised by reduced chloride secretion mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) and Na(+) hyperabsorption through amiloride-sensitive epithelial sodium channels (ENaC). Mutations in CFTR cause the accumulation of thick mucus and dysfunction of mucociliary clearance in the respiratory tract. In this project it was investigated whether Na(+) hyperabsorption is inhibited by the use of antisense oligonucleotides (AON). For functional analyses monolayers of human non-CF and CF nasal epithelial cells were measured in modified Ussing chambers. To analyse the AON effects on the protein level Western blotting analyses were carried out. AON transfection significantly inhibits Na(+) absorption via ENaC in non-CF and CF cells. Furthermore, Western blot analyses demonstrate a suppression of the ENaC protein in AON transfected human non-CF cells. The inhibition of ENaC associated Na(+) absorption by specific AON could offer a new perspective for the regulation of the Na(+) hyperabsorption in CF patients.