Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia |
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Authors: | Moody Mark Pennington Carey Schultz Carsten Caldwell Ray Dinkel Carlo Rossi Michael W McNamara Sharon Widdicombe Jonathan Gabriel Sherif Traynor-Kaplan Alexis E |
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Institution: | Inologic Inc., 101 Elliot Ave. West, Suite 100, Seattle, WA 98119, USA. |
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Abstract: | Amiloride-sensitive, epithelial Na+ channel (ENaC)-mediated, active absorption of Na+ is elevated in the airway epithelium of cystic fibrosis (CF) patients, resulting in excess fluid removal from the airway lumen. This excess fluid/volume absorption corresponds to CF transmembrane regulator-linked defects in ENaC regulation, resulting in the reduced mucociliary clearance found in CF airways. Herein we show that INO-4995, a synthetic analog of the intracellular signaling molecule, D-myo-inositol 3,4,5,6-tetrakisphosphate, inhibits Na+ and fluid absorption across CF airway epithelia, thus alleviating this critical pathology. This conclusion was based on electrophysiological studies, fluid absorption, and 22Na+ flux measurements in CF airway epithelia, contrasted with normal epithelia, and on electrophysiological studies in Madin-Darby canine kidney cells and 3T3 cells overexpressing ENaC. The effects of INO-4995 were long-lasting, dose-dependent, and more pronounced in epithelia from CF patients vs. controls. These findings support preclinical development of INO-4995 for CF treatment and demonstrate for the first time the therapeutic potential of inositol polyphosphate derivatives. epithelial Na+ channels; fluid absorption |
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