title: Airway delivery of low-dose miglustat normalizes nasal potential difference in F508del cystic fibrosis mice.
abstract: BACKGROUND
  N-butyldeoxynojyrimicin (NB-DNJ, miglustat [Zavesca]) an approved drug for treating Gaucher disease, was reported to be able to correct the defective trafficking of the F508del-CFTR protein.
  
  
  OBJECTIVE
  To evaluate the efficacy of in vivo airway delivery of miglustat for restoring ion transport in cystic fibrosis (CF).
  
  
  METHODS
  We used nasal transepithelial potential difference (PD) as a measure of sodium and chloride transport. The effect of nasal instillation of a single dose of miglustat was investigated in F508del, cftr knockout and normal homozygous mice. The galactose iminosugar analog N-butyldeoxygalactonojirimycin (NB-DGJ) was used as a placebo.
  
  
  RESULTS
  In F508del mice, sodium conductance (evaluated by basal hyperpolarization) and chloride conductance (evaluated by perfusing the nasal mucosa with chloride-free solution in the presence of amiloride and forskolin) were normalized 1 hour after an intranasal dose of 50 picomoles of miglustat. Chloride conductance in the presence of 200 microM 4-4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS), an inhibitor of alternative chloride channels, was much higher after miglustat than after placebo. In cftr knockout mice, a normalizing effect was observed on sodium but not on chloride conductance.
  
  
  CONCLUSIONS
  Our results provide clear evidence that nasal delivery of miglustat, at picomolar doses, normalizes sodium and Cftr-dependent chloride transport in F508del transgenic mice; they highlight the potential of topical miglustat as a therapy for CF.
authors.affiliation: Department of Clinical Chemistry, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Bob
authors.initials: B
authors.lastname: Lubamba
authors.forename: Jean
authors.initials: J
authors.lastname: Lebacq
authors.forename: Patrick
authors.initials: P
authors.lastname: Lebecque
authors.forename: Rita
authors.initials: R
authors.lastname: Vanbever
authors.forename: Anissa
authors.initials: A
authors.lastname: Leonard
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
authors.forename: Teresinha
authors.initials: T
authors.lastname: Leal
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000281:Administration, Intranasal; D000818:Animals; D018118:Chloride Channels / Q000187:drug effects*; D003550:Cystic Fibrosis / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D051379:Mice; D018345:Mice, Knockout; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D018118:Chloride Channels; D004791:Enzyme Inhibitors; D015222:Sodium Channels; D017485:1-Deoxynojirimycin; C059896:miglustat