Published ahead of print on March 8, 2007, doi:10.1165/rcmb.2006-0173OC Am. J. Respir. Cell Mol. Biol., Volume 37, Number 1, July 2007, 57-66 A more recent version of this article appeared on July 1, 2007
Submitted on May 16, 2006 No Detectable Improvements in CFTR by Nasal Aminoglycosides in CF Patients with Stop MutationsJohn P Clancy1*,1 Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA; The Cystic Fibrosis Foundation Therapeutic Development Network, USA, 2 Department of Medicine and Pediatrics, University of Washington, Seattle, WA, USA; The Cystic Fibrosis Foundation Therapeutic Development Network, USA, 3 Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA; The Cystic Fibrosis Foundation Therapeutic Development Network, USA, 4 Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA; The Cystic Fibrosis Foundation Therapeutic Development Network, USA, 5 Department of Pediatrics, Stanford University, Palo Alto, CA, USA; The Cystic Fibrosis Foundation Therapeutic Development Network, USA, 6 Department of Medicine, University of North Carolina, Chapel Hill, NC, USA; The Cystic Fibrosis Foundation Therapeutic Development Network, USA, 7 Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA * To whom correspondence should be addressed. E-mail: jpclancy{at}peds.uab.edu.
Cystic fibrosis (CF) is an autosomal recessive disorder caused by many types of genetic defects including premature stop codons. Gentamicin can suppress stop mutations in CFTR in vitro and in vivo, leading to improvements in CFTR-dependent ion transport and protein localization to the apical surface of respiratory epithelial cells. The primary objective of this study was to test whether nasally administered gentamicin or tobramycin could suppress premature stop mutations in CFTR, resulting in full-length, functional protein. A secondary objective was to obtain data to aid in the design of multi-center trials using the nasal potential difference as a study endpoint. A multi-center study was conducted in two cohorts of CF patients, those heterozygous for stop mutations in the CFTR gene and those without nonsense mutations, to investigate the effects of both gentamicin and tobramycin administered over a 28-day period on sequential nasal potential difference and airway cell immunofluorescence endpoints. Eleven CF patients with stop mutations were enrolled in a randomized, double-blinded cross-over fashion to receive each drug, while 18 CF subjects without stop mutations were randomized 1:1 in a parallel fashion to receive one drug. Following demonstration of drug delivery, neither aminoglycoside produced detectable changes in nasal ion transport or CFTR localization in brushed cells from either study group. These results with first generation suppressive agents suggest the need for improved drug delivery methods and/or more potent suppressors of nonsense mutations to confer CFTR correction in CF subjects heterozygous for nonsense mutations.
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