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Airway delivery of low-dose miglustat normalizes nasal potential difference in F508del cystic fibrosis mice.
Am J Respir Crit Care Med. 2009 Jun 01; 179(11):1022-8.AJ

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.

Authors+Show Affiliations

Department of Clinical Chemistry, Université Catholique de Louvain, Brussels, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19299496

Citation

Lubamba, Bob, et al. "Airway Delivery of Low-dose Miglustat Normalizes Nasal Potential Difference in F508del Cystic Fibrosis Mice." American Journal of Respiratory and Critical Care Medicine, vol. 179, no. 11, 2009, pp. 1022-8.
Lubamba B, Lebacq J, Lebecque P, et al. Airway delivery of low-dose miglustat normalizes nasal potential difference in F508del cystic fibrosis mice. Am J Respir Crit Care Med. 2009;179(11):1022-8.
Lubamba, B., Lebacq, J., Lebecque, P., Vanbever, R., Leonard, A., Wallemacq, P., & Leal, T. (2009). Airway delivery of low-dose miglustat normalizes nasal potential difference in F508del cystic fibrosis mice. American Journal of Respiratory and Critical Care Medicine, 179(11), 1022-8. https://doi.org/10.1164/rccm.200901-0049OC
Lubamba B, et al. Airway Delivery of Low-dose Miglustat Normalizes Nasal Potential Difference in F508del Cystic Fibrosis Mice. Am J Respir Crit Care Med. 2009 Jun 1;179(11):1022-8. PubMed PMID: 19299496.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Airway delivery of low-dose miglustat normalizes nasal potential difference in F508del cystic fibrosis mice. AU - Lubamba,Bob, AU - Lebacq,Jean, AU - Lebecque,Patrick, AU - Vanbever,Rita, AU - Leonard,Anissa, AU - Wallemacq,Pierre, AU - Leal,Teresinha, Y1 - 2009/03/19/ PY - 2009/3/21/entrez PY - 2009/3/21/pubmed PY - 2009/6/24/medline SP - 1022 EP - 8 JF - American journal of respiratory and critical care medicine JO - Am. J. Respir. Crit. Care Med. VL - 179 IS - 11 N2 - 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. SN - 1535-4970 UR - https://www.unboundmedicine.com/medline/citation/19299496/Airway_delivery_of_low_dose_miglustat_normalizes_nasal_potential_difference_in_F508del_cystic_fibrosis_mice_ L2 - http://www.atsjournals.org/doi/full/10.1164/rccm.200901-0049OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -