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

• Published in: American Journal of Physiology: Cell Physiology 2005-09, Vol.289 (3), p.C512-C520
• Main Authors: Moody, Mark, Pennington, Carey, Schultz, Carsten, Caldwell, Ray, Dinkel, Carlo, Rossi, Michael W, McNamara, Sharon, Widdicombe, Jonathan, Gabriel, Sherif, Traynor-Kaplan, Alexis E
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Body Fluids - metabolism; Cells, Cultured; Cystic Fibrosis - drug therapy; Cystic Fibrosis - metabolism; Dogs; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Humans; Inositol Phosphates - chemistry; Inositol Phosphates - pharmacology; Kidney - cytology; Membrane Potentials - drug effects; Mice; Nasal Mucosa - cytology; Nasal Mucosa - metabolism; Patch-Clamp Techniques; Prodrugs - chemistry; Prodrugs - pharmacology; Sodium - metabolism
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00591.2004

1 Inologic Inc., Seattle, Washington; 2 University of North Carolina, Chapel Hill, North Carolina; 3 European Molecular Biology Laboratory, Heidelberg, Germany; 4 University of California, Davis, California; and 5 Children'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 22 Na + 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 Address for reprint requests and other correspondence: A. Traynor-Kaplan, Inologic Inc., 101 Elliot Ave. West, Suite 100, Seattle, WA 98119 (e-mail: alexis{at}inologic.com )