Progressive lung damage in cystic fibrosis (CF) has been linked to inadequate airway mucosal hydration. We previously demonstrated that an inositol tetrakisphosphate analog, 1-O-octyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis(propionoxymethyl)ester (INO-4995), regulates airway secretory and absorptive processes, affecting mucosal hydration by prolonged (24 h) inhibition of Na(+) and fluid absorption in CF human nasal epithelia (CFHNE). The objectives of this study were to further assess clinical potential of INO-4995 in CF through ascertaining in vivo activity in mice with CF, determining the effects of repeated administration on potency and determining cytoplasmic half-life. Uptake and metabolism of [(3)H]INO-4995 was monitored with HPLC to calculate intracellular half-life. INO-4995 was administered in vitro repeatedly over 4 to 8 days to CFHNE. Fluid absorption was assessed by blue dextran exclusion, and basal short-circuit current was measured in Ussing chambers. INO-4995 (1-100 microg/kg) was dosed intranasally either as a single dose or once per day over 4 days to gut-corrected CF mice. [(3)H]INO-4995 was rapidly taken up by epithelial cultures and converted to the active drug, which had a half-life of 40 hours. Repeated daily application of INO-4995 to CFHNE lowered the effective concentration for inhibition of fluid absorption and amiloride-sensitive short-circuit current in cultured CFHNE, and reduced nasal potential difference to nearly control levels in gut-corrected CF mice. Ca(2+)-activated Cl(-) channel activity was also boosted in cultures. Mouse nasal levels fell from abnormal levels to within 2 muA of normal with repeated exposure to 0.8 microg/kg over 4 days. These data support further development of INO-4995 for the treatment of CF.

2005-12-01·Expert Opinion on Therapeutic Targets2区 · 医学

Can intervention in inositol phosphate signalling pathways improve therapy for cystic fibrosis?

2区 · 医学

Review

作者: Shears, Stephen B

Airway epithelial cells from cystic fibrosis (CF) individuals cannot secrete adequate Cl- through cystic fibrosis transmembrane regulator, and their Na+ channel (ENaC) activity is increased so that excessive Na+ and water is absorbed from the lumen. These aberrant transport activities can, at least partly, be compensated by pharmacologically increasing the activities of Ca2+-activated Cl- channels (CaCCs). The therapeutic value of this approach is currently being examined in clinical trials of candidate CF drugs such as INS-37217 (Inspire Pharmaceuticals) and Moli1901 (Lantibio, Inc.). This review argues that these drug development programmes will be helped if one can fully understand how the CaCCs are inhibited by inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4), so that there can be pharmacological intervention in this process. Furthermore, genes that encode enzymes controlling Ins(3,4,5,6)P4 metabolism should be viewed as impacting upon CaCC activity; this, in turn, may influence the severity of the CF condition. Expression profiling of genes that regulate inositol phosphate metabolism may also illuminate variability in patient response to treatment regimens that target CaCCs. Compounds have been developed that can activate CaCCs by antagonising their inhibition by Ins(3,4,5,6)P4. One member of this drug family (INO-4995; Inologic) was recently shown to inhibit ENaC, thereby reducing fluid absorbtion by airway epithelial cells.

2005-09-01·American Journal of Physiology-Cell Physiology3区 · 生物学

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

3区 · 生物学

Article

作者: McNamara, Sharon ; Widdicombe, Jonathan ; Moody, Mark ; Pennington, Carey ; Caldwell, Ray ; Rossi, Michael W. ; Dinkel, Carlo ; Schultz, Carsten ; Gabriel, Sherif ; Traynor-Kaplan, Alexis E.

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.

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