1. Am J Respir Crit Care Med. 2009 Jun 1;179(11):1022-8. Epub 2009 Mar 19.

Airway delivery of low-dose miglustat normalizes nasal potential difference in
F508del cystic fibrosis mice.

Lubamba B, Lebacq J, Lebecque P, Vanbever R, Leonard A, Wallemacq P, Leal T.

Department of Clinical Chemistry, Université Catholique de Louvain, Brussels,
Belgium.

RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND
MAIN 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.

PMID: 19299496 [PubMed - indexed for MEDLINE]