Inpharma 1409 - 18 Oct 2003 Gentamicin corrects cellular phenotype in cystic fibrosis Gentamicin, applied topically to the nasal epithelium of patients with cystic fibrosis (CF), corrects the electrophysiological abnormalities caused by cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, report researchers from Israel and the US. 1 Nineteen patients with stop mutations in CFTR and five patients homozygous for the ∆F508 mutation (controls) instilled gentamicin [‘Garamycin’] and placebo, two drops in each nostril 3 times daily (total daily dose of 900µg), for 14 days each in a crossover fashion. Among the 19 patients with stop mutations, 14 days of gentamicin administration resulted in a significant reduction in the mean basal nasal potential difference, from –45mV at baseline to –34mV, and a significant response to chloride-free isoproterenol solution, from 0mV to –5mV; no such changes were seen among the controls. Furthermore, analysis of the "read through" of premature nonsense codons in two of the patients with the ∆F508/W1282X genotype who responded to gentamicin revealed a significant increase in peripheral and surface staining for CFTR in the nasal epithelial cells. The immunostaining was similar to that observed in the controls, note the researchers. The above-mentioned study "illustrates the potential importance of pharmacologic modulation of dysfunctional CFTR", say Drs Gergely Lukacs and Peter Durie from the Hospital for Sick Children, Toronto, Canada. 2 They also comment that high-throughput screening of large libraries of compounds, using a cell- based functional assay, has "potential value . . . for identifying pharmacologic agents that will correct the cellular phenotype in cystic fibrosis and other diseases that 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 of Medicine 349: 1433-1441, No. 15, 9 Oct 2003. 2. Lukacs GL, et al. Pharmacologic approaches to correcting the basic defect in cystic fibrosis. New England Journal of Medicine 349: 1401-1404, No. 15, 9 Oct 2003. 800969222 1 Inpharma 18 Oct 2003 No. 1409 1173-8324/10/1409-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved

Gentamicin corrects cellular phenotype in cystic fibrosis

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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.

800969222