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

an approved drug for treating Gaucher disease, was reported to be able to correct the defective traffickingof the F508del-CFTRprotein. 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 ofmiglustat was investigated in F508del, cftr knockout and normal homozygous mice. The galactose imino-sugar analogN-butyldeoxygalactonojirimycin (NB-DGJ)was used as a placebo. Measurements and Main Results: In F508del mice, sodium conduc-tance (evaluated by basal hyperpolarization) and chloride conduc-tance (evaluated by perfusing the nasal mucosa with chloride-free solution in thepresenceof amiloride and forskolin)were normalized 1hour after an intranasaldoseof50picomolesofmiglustat.Chloride conductance in the presence of 200mM4-49-diisothiocyanostilbene-2,29-disulphonic acid (DIDS), an inhibitor of alternative chloride channels, wasmuch higher aftermiglustat than after placebo. In cftr knockoutmice, anormalizingeffectwasobservedon sodiumbutnot on chloride conductance. Conclusions: Our results provide clear evidence that nasal delivery of miglustat, at picomolar doses, normalizes sodium and Cftr-depen-dent chloride transport in F508del transgenic mice; they highlight the potential of topical miglustat as a therapy for CF