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A Cystic Fibrosis Respiratory Epithelial Cell Chronically Treated by Miglustat Acquires a Non–Cystic Fibrosis–Like Phenotype

¹ Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, Centre National de la Recherche Scientifique, Poitiers, France

Correspondence and requests for reprints should be addressed to Frédéric Becq, IPBC, Université de Poitiers, 40 Avenue du Recteur Pineau, 86022 Poitiers, France. E-mail: frederic.becq{at}univ-poitiers.fr

Cystic fibrosis (CF) is a fatal, autosomal and recessive genetic disease that is mainly due to inactivating mutations in the chloride channel CF transmembrane conductance regulator (CFTR). Sodium hyperabsorption by the airways, profound lung inflammation, and dysregulation of calcium homeostasis, are presumably causally related to loss of CFTR-dependent chloride function in patients with CF. Miglustat (N-butyldeoxynojirimycin, Zavesca), an inhibitor of the -1,2 glucosidase, has been proposed for clinical use in CF because of its effect as a corrector of the defective trafficking of F508del-CFTR. In the present study, we show that daily treatment for 2 months with low concentrations of miglustat on the human CF nasal epithelial cell line, JME/CF15 (F508del/F508del-CFTR), results in progressive, stable, reversible, and sustained correction of F508del-CFTR trafficking, down-regulation of sodium hyperabsorption, and regulation of the calcium homeostasis. In conclusion, we provide here the first evidence that a respiratory CF cell can acquire a non–CF-like phenotype when chronically treated with low concentrations of a pharmacological drug.

Key Words: F508del–cystic fibrosis transmembrane conductance regulator • epithelial Na⁺ channel • calcium homeostasis • sodium hyperabsorption • miglustat

CLINICAL RELEVANCE We show that a respiratory cystic fibrosis (CF) cell can acquire a non–CF-like phenotype when chronically treated with low-concentration miglustat. This drug is thus attractive as a potential pharmacologic therapy for patients with CF who have at least one F508del-CF transmembrane conductance regulator allele.