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TRANSLATIONAL PHYSIOLOGY

Inositol polyphosphate derivative inhibits Na⁺ transport and improves fluid dynamics in cystic fibrosis airway epithelia

¹Inologic Inc., Seattle, Washington; ²University of North Carolina, Chapel Hill, North Carolina; ³European Molecular Biology Laboratory, Heidelberg, Germany; ⁴University of California, Davis, California; and ⁵Children's Hospital, Seattle, Washington

Submitted 2 December 2004 ; accepted in final form 22 April 2005

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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