Gentamicin corrects cellular phenotype in cystic fibrosis

Inpharma 1409 - 18 Oct 2003

Gentamicin corrects cellularphenotype in cystic fibrosis

Gentamicin, applied topically to the nasal epitheliumof patients with cystic fibrosis (CF), corrects theelectrophysiological abnormalities caused by cysticfibrosis transmembrane conductance regulator (CFTR)dysfunction, report researchers from Israel and the US.1

Nineteen patients with stop mutations in CFTR andfive patients homozygous for the ∆F508 mutation(controls) instilled gentamicin [‘Garamycin’] andplacebo, two drops in each nostril 3 times daily (totaldaily dose of 900µg), for 14 days each in a crossoverfashion.

Among the 19 patients with stop mutations, 14 daysof gentamicin administration resulted in a significantreduction in the mean basal nasal potential difference,from –45mV at baseline to –34mV, and a significantresponse to chloride-free isoproterenol solution, from0mV to –5mV; no such changes were seen among thecontrols. Furthermore, analysis of the "read through" ofpremature nonsense codons in two of the patients withthe ∆F508/W1282X genotype who responded togentamicin revealed a significant increase in peripheraland surface staining for CFTR in the nasal epithelial cells.The immunostaining was similar to that observed in thecontrols, note the researchers.

The above-mentioned study "illustrates the potentialimportance of pharmacologic modulation ofdysfunctional CFTR", say Drs Gergely Lukacs and PeterDurie from the Hospital for Sick Children, Toronto,Canada.2 They also comment that high-throughputscreening of large libraries of compounds, using a cell-based functional assay, has "potential value . . . foridentifying pharmacologic agents that will correct thecellular phenotype in cystic fibrosis and other diseasesthat are caused by misfolding".1. Wilschanski M, et al. Gentamicin-induced correction of CFTR function in

patients with cystic fibrosis and CFTR stop mutations. New England Journal ofMedicine 349: 1433-1441, No. 15, 9 Oct 2003.

2. Lukacs GL, et al. Pharmacologic approaches to correcting the basic defect incystic fibrosis. New England Journal of Medicine 349: 1401-1404, No. 15, 9 Oct2003.

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Inpharma 18 Oct 2003 No. 14091173-8324/10/1409-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved