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Airway Delivery of Low-Dose Miglustat Normalizes Nasal Potential Difference in F508del Cystic Fibrosis Mice

Departments of ¹ Clinical Chemistry, ² Cell Physiology, ³ Pharmaceutical Technology, and ⁴ Pediatric Pulmonology, Université Catholique de Louvain, Brussels, Belgium

Correspondence and requests for reprints should be addressed to Teresinha Leal, M.D., Ph.D., Department of Clinical Chemistry, St. Luc University Hospital, 10 Av Hippocrate, B-1200 Brussels, Belgium. E-mail: teresinha.leal{at}uclouvain.be

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 µM 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.

Key Words: cystic fibrosis • miglustat • chloride transport • sodium transport • nasal potential difference

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Miglustat, an approved oral therapy for Gaucher disease, has been shown to partially correct defective trafficking of F508del-CFTR. What This Study Adds to the Field Nasal deposition of miglustat improves both chloride and sodium transport in F508del-CFTR mice, warranting further studies of topical miglustat as potential therapy for cystic fibrosis.