A pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene containing a premature termination signal are expected to produce little or no CFTR chloride channels. It has been shown in vitro, that aminoglycoside antibiotics can increase the frequency of erroneous insertion of nonsense codons hence permitting the translation of CFTR alleles carrying missense mutations to continue reading to the end of the gene. This led to the appearance of functional CFTR channels at the apical plasma membrane. The aim of this research was to determine if topical application of gentamicin to the nasal epithelium of patients with cystic fibrosis (CF) carrying stop mutations can express, in vivo, functional CFTR channels. Nine CF patients carrying stop mutations (mean age 23 +/- 11 yr, range 12 to 46 yr) received gentamicin drops (0.3%, 3 mg/ml) three times daily intranasally for a total of 14 d. Nasal potential difference (PD) was measured before and after the treatment. Before gentamicin application all the patients had abnormal nasal PD typical of CF. After gentamicin treatment, significant repolarization of the nasal epithelium representing chloride transport was increased from -1 +/- 1 mV to -10 +/- 11 mV (p < 0. 001). In conclusion, gentamicin may influence the underlying chloride transport abnormality in patients with CF carrying stop mutations.

[1]  H. Sweeney,et al.  Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. , 1999, The Journal of clinical investigation.

[2]  S. Durham,et al.  Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial , 1999, The Lancet.

[3]  B. Kerem,et al.  The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C-->T mutation. , 1998, Genomics.

[4]  K. Jacobson,et al.  Direct Activation of Cystic Fibrosis Transmembrane Conductance Regulator Channels by 8-Cyclopentyl-1,3-dipropylxanthine (CPX) and 1,3-Diallyl-8-cyclohexylxanthine (DAX)* , 1998, The Journal of Biological Chemistry.

[5]  Y. Wang,et al.  Assessment of the efficacy of in vivo CFTR protein replacement therapy in CF mice. , 1998, Human gene therapy.

[6]  P. Zeitlin,et al.  A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function. , 1998, American journal of respiratory and critical care medicine.

[7]  J. Clancy,et al.  Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line , 1997, Nature Medicine.

[8]  J. Morris,et al.  Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelia in vivo. , 1997, The Journal of clinical investigation.

[9]  B. Kerem,et al.  A cystic fibrosis transmembrane conductance regulator splice variant with partial penetrance associated with variable cystic fibrosis presentations. , 1997, American journal of respiratory and critical care medicine.

[10]  J. Clancy,et al.  Relationship between airway ion transport and a mild pulmonary disease mutation in CFTR. , 1997, American journal of respiratory and critical care medicine.

[11]  M. Drumm,et al.  In vivo activation of the cystic fibrosis transmembrane conductance regulator mutant deltaF508 in murine nasal epithelium. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Bedwell,et al.  Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations , 1996, Nature Medicine.

[13]  R. Gibson,et al.  Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. , 1996, The Journal of clinical investigation.

[14]  P. Hu,et al.  A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. , 1995, The New England journal of medicine.

[15]  D. Bedwell,et al.  The efficiency of translation termination is determined by a synergistic interplay between upstream and downstream sequences in Saccharomyces cerevisiae. , 1995, Journal of molecular biology.

[16]  Chris M. Brown,et al.  The identity of the base following the stop codon determines the efficiency of in vivo translational termination in Escherichia coli. , 1995, The EMBO journal.

[17]  J C Olsen,et al.  A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. , 1994, The New England journal of medicine.

[18]  T. Flotte,et al.  Both CFTR and outwardly rectifying chloride channels contribute to cAMP-stimulated whole cell chloride currents. , 1994, The American journal of physiology.

[19]  B. Kerem,et al.  Correlation between genotype and phenotype in patients with cystic fibrosis. , 1994, The New England journal of medicine.

[20]  R. Boucher,et al.  CFTR and outward rectifying chloride channels are distinct proteins with a regulatory relationship , 1993, Nature.

[21]  T. Flotte,et al.  Defective regulation of outwardly rectifying Cl− channels by protein kinase A corrected by insertion of CFTR , 1992, Nature.

[22]  M. Corey,et al.  Genetic determination of exocrine pancreatic function in cystic fibrosis. , 1992, American journal of human genetics.

[23]  R. Goldman,et al.  Influence of codon context on UGA suppression and readthrough. , 1992, Journal of Molecular Biology.

[24]  A. Hamosh,et al.  Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis. , 1991, The Journal of clinical investigation.

[25]  J. Buchanan,et al.  Aminoglycoside antibiotic treatment of human fibroblasts: intracellular accumulation, molecular changes and the loss of ribosomal accuracy. , 1987, European journal of cell biology.

[26]  J. Burke,et al.  Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin. , 1985, Nucleic acids research.

[27]  J. Davies,et al.  Phenotypic suppression and misreading in Saccharomyces cerevisiae , 1979, Nature.

[28]  J. Davies,et al.  Misreading of RNA codewords induced by aminoglycoside antibiotics. , 1965, Molecular pharmacology.

[29]  L. Gorini,et al.  PHENOTYPIC REPAIR BY STREPTOMYCIN OF DEFECTIVE GENOTYPES IN E. COLI. , 1964, Proceedings of the National Academy of Sciences of the United States of America.

[30]  B. Kerem,et al.  Cystic fibrosis in Jews: frequency and mutation distribution. , 1997, Genetic testing.

[31]  B. Kerem,et al.  The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. , 1997, American journal of human genetics.

[32]  J. Cheadle,et al.  Population variation of common cystic fibrosis mutations , 1994 .

[33]  L. Tsui,et al.  Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: A report from the cystic fibrosis genetic analysis consortium , 1992, Human mutation.

[34]  B. Kerem,et al.  Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. , 1992, American journal of human genetics.

[35]  J. Gustafson,et al.  Cystic Fibrosis , 2009, Journal of the Iowa Medical Society.