Format

Send to

Choose Destination
Am J Respir Crit Care Med. 2009 Jun 1;179(11):1022-8. doi: 10.1164/rccm.200901-0049OC. Epub 2009 Mar 19.

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

Author information

1
Department of Clinical Chemistry, Université Catholique de Louvain, Brussels, Belgium.

Abstract

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
DOI:
10.1164/rccm.200901-0049OC
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center