title: Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia.
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 (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.
authors.affiliation: Inologic Inc., 101 Elliot Ave. West, Suite 100, Seattle, WA 98119, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Moody
authors.forename: Carey
authors.initials: C
authors.lastname: Pennington
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz
authors.forename: Ray
authors.initials: R
authors.lastname: Caldwell
authors.forename: Carlo
authors.initials: C
authors.lastname: Dinkel
authors.forename: Michael W
authors.initials: MW
authors.lastname: Rossi
authors.forename: Sharon
authors.initials: S
authors.lastname: McNamara
authors.forename: Jonathan
authors.initials: J
authors.lastname: Widdicombe
authors.forename: Sherif
authors.initials: S
authors.lastname: Gabriel
authors.forename: Alexis E
authors.initials: AE
authors.lastname: Traynor-Kaplan
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009297:Nasal Mucosa / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*
chemical_list: C503977:INO-4995; D007295:Inositol Phosphates; D011355:Prodrugs; D012964:Sodium