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No Detectable Improvements in Cystic Fibrosis Transmembrane Conductance Regulator by Nasal Aminoglycosides in Patients with Cystic Fibrosis with Stop Mutations

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine and Pediatrics, University of Washington, Seattle, Washington; Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Department of Pediatrics, Stanford University, Palo Alto, California; Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; and The Cystic Fibrosis Foundation Therapeutic Development Network

Correspondence and requests for reprints should be addressed to J. P. Clancy, M.D., Department of Pediatrics, University of Alabama at Birmingham, 620 ACC, 1600 7th Avenue South, Birmingham, AL 35233. 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 CF transmembrane conducatnce regulator (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 multicenter trials using the nasal potential difference as a study endpoint. A multicenter study was conducted in two cohorts of patients with CF, 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-d period on sequential nasal potential difference and airway cell immunofluorescence endpoints. Eleven patients with CF with stop mutations were enrolled in a randomized, double-blinded, crossover fashion to receive each drug, while 18 subjects with CF without stop mutations were randomized 1:1 in a parallel fashion to receive one drug. After 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 subjects with CF heterozygous for nonsense mutations. The study provides valuable information on parameters of the nasal potential difference measurements for use in future multicenter clinical trials.

Key Words: cystic fibrosis • nonsense mutations • chloride secretion • nasal potential difference

CLINICAL RELEVANCE This study demonstrates that not all premature stop mutations are equally sensitive to suppression in vivo, and will help researchers design clinical trials to detect CFTR activity.

 

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