FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 349:1433-1441 October 9, 2003 Number 15 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Perspective by Lukacs, G. L. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene containing a premature termination signal cause a deficiency or absence of functional chloride-channel activity. Aminoglycoside antibiotics can suppress premature termination codons, thus permitting translation to continue to the normal end of the transcript. We assessed whether topical administration of gentamicin to the nasal epithelium of patients with cystic fibrosis could result in the expression of functional CFTR channels.

Methods In a double-blind, placebo-controlled, crossover trial, patients with stop mutations in CFTR or patients homozygous for the F508 mutation received two drops containing gentamicin (0.3 percent, or 3 mg per milliliter) or placebo in each nostril three times daily for two consecutive periods of 14 days. Nasal potential difference was measured at base line and after each treatment period. Nasal epithelial cells were obtained before and after gentamicin treatment from patients carrying stop mutations, and the C-terminal of surface CFTR was stained.

Results Gentamicin treatment caused a significant reduction in basal potential difference in the 19 patients carrying stop mutations (from –45±8 to –34±11 mV, P=0.005) and a significant response to chloride-free isoproterenol solution (from 0±3.6 to –5±2.7 mV, P<0.001). This effect of gentamicin on nasal potential difference occurred both in patients who were homozygous for stop mutations and in those who were heterozygous, but not in patients who were homozygous for F508. After gentamicin treatment, a significant increase in peripheral and surface staining for CFTR was observed in the nasal epithelial cells of patients carrying stop mutations.

Conclusions In patients with cystic fibrosis who have premature stop codons, gentamicin can cause translational "read through," resulting in the expression of full-length CFTR protein at the apical cell membrane, and thus can correct the typical electrophysiological abnormalities caused by CFTR dysfunction.

Source Information

From the Department of Pediatrics, Cystic Fibrosis Center, Shaare Zedek Medical Center (M.W., Y. Yaacov, E.K.), and Hadassah University Hospital, Mount Scopus (E.K.), Hebrew University Medical School, Jerusalem, Israel; the Cystic Fibrosis Center, Sheba Medical Center, Tel Hashomer, Israel (Y. Yahav); the Graub Cystic Fibrosis Center, Schneider Children's Medical Center of Israel, Petah Tikva, Israel (H.B.); the Cystic Fibrosis Center, Rambam Medical Center, Haifa, Israel (L.B.); the Cystic Fibrosis Center, Carmel Medical Center, Haifa, Israel (J.R.); the Cystic Fibrosis Center, Soroka Medical Center, Beer Sheva, Israel (M.A.); the Department of Medical Statistics (T.B.-A.) and the Department of Genetics, Life Sciences Institute (L.S., B.K.), Hebrew University, Jerusalem, Israel; and the Department of Cell Biology and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham (Z.B.).

Full Text of this Article

Related Letters:

Gentamicin and CFTR
Kida Y.
Extract | Full Text | PDF  
N Engl J Med 2003; 349:2570, Dec 25, 2003. Correspondence

This article has been cited by other articles:

• Schulze-Bahr, E. (2009). Making sense in a nonsense reading frame: suppression of cardiac sodium channel dysfunction. Cardiovasc Res 83: 423-424 [Full Text]  
• Balfour-Lynn, I. M (2009). Cystic fibrosis papers of the year 2008. JRSM 102: 29-35 [Full Text]  
• Heier, C. R., DiDonato, C. J. (2009). Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo. Hum Mol Genet 18: 1310-1322 [Abstract] [Full Text]  
• Du, M., Keeling, K. M., Fan, L., Liu, X., Bedwell, D. M. (2009). Poly-L-aspartic Acid Enhances and Prolongs Gentamicin-mediated Suppression of the CFTR-G542X Mutation in a Cystic Fibrosis Mouse Model. J. Biol. Chem. 284: 6885-6892 [Abstract] [Full Text]  
• Moosajee, M., Gregory-Evans, K., Ellis, C. D., Seabra, M. C., Gregory-Evans, C. Y. (2008). Translational bypass of nonsense mutations in zebrafish rep1, pax2.1 and lamb1 highlights a viable therapeutic option for untreatable genetic eye disease. Hum Mol Genet 17: 3987-4000 [Abstract] [Full Text]  
• Halwani, M., Yebio, B., Suntres, Z. E., Alipour, M., Azghani, A. O., Omri, A. (2008). Co-encapsulation of gallium with gentamicin in liposomes enhances antimicrobial activity of gentamicin against Pseudomonas aeruginosa. J Antimicrob Chemother 62: 1291-1297 [Abstract] [Full Text]  
• Azimov, R., Abuladze, N., Sassani, P., Newman, D., Kao, L., Liu, W., Orozco, N., Ruchala, P., Pushkin, A., Kurtz, I. (2008). G418-mediated ribosomal read-through of a nonsense mutation causing autosomal recessive proximal renal tubular acidosis. Am. J. Physiol. Renal Physiol. 295: F633-F641 [Abstract] [Full Text]  
• Du, M., Liu, X., Welch, E. M., Hirawat, S., Peltz, S. W., Bedwell, D. M. (2008). PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proc. Natl. Acad. Sci. USA 105: 2064-2069 [Abstract] [Full Text]  
• Scott-Ward, T. S., Cai, Z., Dawson, E. S., Doherty, A., Carina Da Paula, A., Davidson, H., Porteous, D. J., Wainwright, B. J., Amaral, M. D., Sheppard, D. N., Boyd, A. C. (2007). Chimeric constructs endow the human CFTR Cl channel with the gating behavior of murine CFTR. Proc. Natl. Acad. Sci. USA 104: 16365-16370 [Abstract] [Full Text]  
• Yaakov, Y., Kerem, E., Yahav, Y., Rivlin, J., Blau, H., Bentur, L., Aviram, M., Picard, E., Bdolah-Abram, T., Wilschanski, M. (2007). Reproducibility of Nasal Potential Difference Measurements in Cystic Fibrosis. Chest 132: 1219-1226 [Abstract] [Full Text]  
• Yang, C., Feng, J., Song, W., Wang, J., Tsai, B., Zhang, Y., Scaringe, W. A., Hill, K. A., Margaritis, P., High, K. A., Sommer, S. S. (2007). A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin. Proc. Natl. Acad. Sci. USA 104: 15394-15399 [Abstract] [Full Text]  
• Rowe, S. M., Varga, K., Rab, A., Bebok, Z., Byram, K., Li, Y., Sorscher, E. J., Clancy, J. P. (2007). Restoration of W1282X CFTR Activity by Enhanced Expression. Am. J. Respir. Cell Mol. Bio. 37: 347-356 [Abstract] [Full Text]  
• Ramsey, B. W. (2007). Outcome Measures for Development of New Therapies in Cystic Fibrosis: Are We Making Progress and What Are the Next Steps?. Proc Am Thorac Soc 4: 367-369 [Full Text]  
• Rowe, S. M., Accurso, F., Clancy, J. P. (2007). Detection of Cystic Fibrosis Transmembrane Conductance Regulator Activity in Early-Phase Clinical Trials. Proc Am Thorac Soc 4: 387-398 [Abstract] [Full Text]  
• Clancy, J. P., Rowe, S. M., Bebok, Z., Aitken, M. L., Gibson, R., Zeitlin, P., Berclaz, P., Moss, R., Knowles, M. R., Oster, R. A., Mayer-Hamblett, N., Ramsey, B. (2007). No Detectable Improvements in Cystic Fibrosis Transmembrane Conductance Regulator by Nasal Aminoglycosides in Patients with Cystic Fibrosis with Stop Mutations. Am. J. Respir. Cell Mol. Bio. 37: 57-66 [Abstract] [Full Text]  
• Aznarez, I., Zielenski, J., Rommens, J. M, Blencowe, B. J, Tsui, L.-C. (2007). Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X. J. Med. Genet. 44: 341-346 [Abstract] [Full Text]  
• Alton, E. W. F. W., Davies, J. C., Geddes, D. M. (2007). Biomarkers for Cystic Fibrosis: Are We Progressing?. Am. J. Respir. Crit. Care Med. 175: 750-751 [Full Text]  
• Hirawat, S., Welch, E. M., Elfring, G. L., Northcutt, V. J., Paushkin, S., Hwang, S., Leonard, E. M., Almstead, N. G., Ju, W., Peltz, S. W., Miller, L. L. (2007). Safety, Tolerability, and Pharmacokinetics of PTC124, a Nonaminoglycoside Nonsense Mutation Suppressor, Following Single- and Multiple-Dose Administration to Healthy Male and Female Adult Volunteers. J Clin Pharmacol 47: 430-444 [Abstract] [Full Text]  
• Bush, A. (2007). Update in Pediatric Lung Disease 2006. Am. J. Respir. Crit. Care Med. 175: 532-540 [Full Text]  
• High, K. A. (2007). Update on Progress and Hurdles in Novel Genetic Therapies for Hemophilia. ASH Education Book 2007: 466-472 [Abstract] [Full Text]  
• Wilschanski, M., Dupuis, A., Ellis, L., Jarvi, K., Zielenski, J., Tullis, E., Martin, S., Corey, M., Tsui, L.-C., Durie, P. (2006). Mutations in the Cystic Fibrosis Transmembrane Regulator Gene and In Vivo Transepithelial Potentials. Am. J. Respir. Crit. Care Med. 174: 787-794 [Abstract] [Full Text]  
• Sandoval, R. M., Reilly, J. P., Running, W., Campos, S. B., Santos, J. R., Phillips, C. L., Molitoris, B. A. (2006). A Non-Nephrotoxic Gentamicin Congener That Retains Antimicrobial Efficacy. J. Am. Soc. Nephrol. 17: 2697-2705 [Abstract] [Full Text]  
• Olson, T. M., Alekseev, A. E., Liu, X. K., Park, S., Zingman, L. V., Bienengraeber, M., Sattiraju, S., Ballew, J. D., Jahangir, A., Terzic, A. (2006). Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet 15: 2185-2191 [Abstract] [Full Text]  
• Hornef, N., Olbrich, H., Horvath, J., Zariwala, M. A., Fliegauf, M., Loges, N. T., Wildhaber, J., Noone, P. G., Kennedy, M., Antonarakis, S. E., Blouin, J.-L., Bartoloni, L., Nusslein, T., Ahrens, P., Griese, M., Kuhl, H., Sudbrak, R., Knowles, M. R., Reinhardt, R., Omran, H. (2006). DNAH5 Mutations Are a Common Cause of Primary Ciliary Dyskinesia with Outer Dynein Arm Defects. Am. J. Respir. Crit. Care Med. 174: 120-126 [Abstract] [Full Text]  
• Munnich, A (2006). Advances in genetics: what are the benefits for patients?. J. Med. Genet. 43: 555-556 [Full Text]  
• Kunz, J. B., Neu-Yilik, G., Hentze, M. W., Kulozik, A. E., Gehring, N. H. (2006). Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation. RNA 12: 1015-1022 [Abstract] [Full Text]  
• Handy, D. E., Hang, G., Scolaro, J., Metes, N., Razaq, N., Yang, Y., Loscalzo, J. (2006). Aminoglycosides Decrease Glutathione Peroxidase-1 Activity by Interfering with Selenocysteine Incorporation. J. Biol. Chem. 281: 3382-3388 [Abstract] [Full Text]  
• Schroers, A., Kley, R. A., Stachon, A., Horvath, R., Lochmuller, H., Zange, J., Vorgerd, M. (2006). Gentamicin treatment in McArdle disease: Failure to correct myophosphorylase deficiency. Neurology 66: 285-286 [Full Text]  
• James, P. D., Raut, S., Rivard, G. E., Poon, M.-C., Warner, M., McKenna, S., Leggo, J., Lillicrap, D. (2005). Aminoglycoside suppression of nonsense mutations in severe hemophilia. Blood 106: 3043-3048 [Abstract] [Full Text]  
• Reiniger, N., Ichikawa, J. K., Pier, G. B. (2005). Influence of Cystic Fibrosis Transmembrane Conductance Regulator on Gene Expression in Response to Pseudomonas aeruginosa Infection of Human Bronchial Epithelial Cells. Infect. Immun. 73: 6822-6830 [Abstract] [Full Text]  
• Rowe, S. M., Miller, S., Sorscher, E. J. (2005). Cystic Fibrosis. NEJM 352: 1992-2001 [Full Text]  
• Schrijver, I., Ramalingam, S., Sankaran, R., Swanson, S., Dunlop, C. L.M., Keiles, S., Moss, R. B., Oehlert, J., Gardner, P., Wassman, E. R., Kammesheidt, A. (2005). Diagnostic Testing by CFTR Gene Mutation Analysis in a Large Group of Hispanics: Novel Mutations and Assessment of a Population-Specific Mutation Spectrum. J. Mol. Diagn. 7: 289-299 [Abstract] [Full Text]  
• Correa-Cerro, L S, Wassif, C A, Waye, J S, Krakowiak, P A, Cozma, D, Dobson, N R, Levin, S W, Anadiotis, G, Steiner, R D, Krajewska-Walasek, M, Nowaczyk, M J M, Porter, F D (2005). DHCR7 nonsense mutations and characterisation of mRNA nonsense mediated decay in Smith-Lemli-Opitz syndrome. J. Med. Genet. 42: 350-357 [Full Text]  
• Gras-Le Guen, C., Jarry, A., Vallette, G., Toquet, C., Colombeix, C., Laboisse, C. L., Potel, G., Roze, J-C., Bugnon, D., Debillon, T. (2005). Antibiotic therapy reduces nitrosative stress and programmed cell death in the rabbit foetal lung. Eur Respir J 25: 88-95 [Abstract] [Full Text]  
• Lai, C.-H., Chun, H. H., Nahas, S. A., Mitui, M., Gamo, K. M., Du, L., Gatti, R. A. (2004). Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons. Proc. Natl. Acad. Sci. USA 101: 15676-15681 [Abstract] [Full Text]  
• Sabatino, D. E., Armstrong, E., Edmonson, S., Liu, Y.-L., Pleimes, M., Schuettrumpf, J., Fitzgerald, J., Herzog, R. W., Arruda, V. R., High, K. A. (2004). Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene. Blood 104: 2767-2774 [Abstract] [Full Text]  
• Koehler, D. R., Downey, G. P., Sweezey, N. B., Tanswell, A. K., Hu, J. (2004). Lung Inflammation as a Therapeutic Target in Cystic Fibrosis. Am. J. Respir. Cell Mol. Bio. 31: 377-381 [Abstract] [Full Text]  
• Zeitlin, P. (2004). Can Curcumin Cure Cystic Fibrosis?. NEJM 351: 606-608 [Full Text]  
• Rheault, M. N., Kren, S. M., Thielen, B. K., Mesa, H. A., Crosson, J. T., Thomas, W., Sado, Y., Kashtan, C. E., Segal, Y. (2004). Mouse Model of X-Linked Alport Syndrome. J. Am. Soc. Nephrol. 15: 1466-1474 [Abstract] [Full Text]  
• Sangkuhl, K., Schulz, A., Rompler, H., Yun, J., Wess, J., Schoneberg, T. (2004). Aminoglycoside-mediated rescue of a disease-causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo. Hum Mol Genet 13: 893-903 [Abstract] [Full Text]  
• Kida, Y. (2003). Gentamicin and CFTR. NEJM 349: 2570-2570 [Full Text]