Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia.
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.
Moody
Mark
M
Inologic Inc., 101 Elliot Ave. West, Suite 100, Seattle, WA 98119, USA.
Pennington
Carey
C
Schultz
Carsten
C
Caldwell
Ray
R
Dinkel
Carlo
C
Rossi
Michael W
MW
McNamara
Sharon
S
Widdicombe
Jonathan
J
Gabriel
Sherif
S
Traynor-Kaplan
Alexis E
AE
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*
C503977:INO-4995; D007295:Inositol Phosphates; D011355:Prodrugs; D012964:Sodium