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Detection of Cystic Fibrosis Transmembrane Conductance Regulator Activity in Early-Phase Clinical Trials

¹ Department of Medicine, ² Department of Physiology and Biophysics, ³ Department of Pediatrics, and ⁴ Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama; and ⁵ Department of Pediatrics, University of Colorado, Denver, Colorado

Correspondence and requests for reprints should be addressed to Steven M. Rowe, M.D., M.S.P.H., University of Alabama at Birmingham, THT 215, 1900 University Boulevard, Birmingham, AL 35294-0006. E-mail: smrowe{at}uab.edu

ABSTRACT

Advances in our understanding of cystic fibrosis pathogenesis have led to strategies directed toward treatment of underlying causes of the disease rather than treatments of disease-related symptoms. To expedite evaluation of these emerging therapies, early-phase clinical trials require extension of in vivo cystic fibrosis transmembrane conductance regulator (CFTR)–detecting assays to multicenter trial formats, including nasal potential difference and sweat chloride measurements. Both of these techniques can be used to fulfill diagnostic criteria for the disease, and can discriminate various levels of CFTR function. Full realization of these assays in multicenter clinical trials requires identification of sources of nonbiological intra- and intersite variability, and careful attention to study design and statistical analysis of study-generated data. In this review, we discuss several issues important to the performance of these assays, including efforts to identify and address aspects that can contribute to inconsistent and/or potentially erroneous results. Adjunctive means of detecting CFTR including mRNA expression, immunocytochemical localization, and other methods are also discussed. Recommendations are presented to advance our understanding of these biomarkers and to improve their capacity to predict cystic fibrosis outcomes.

Key Words: ion transport • cystic fibrosis transmembrane conductance regulator biomarkers • cystic fibrosis therapy • nasal potential difference • sweat chloride

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				S. H. Donaldson, T. E. Corcoran, B. L. Laube, and W. D. Bennett Mucociliary Clearance as an Outcome Measure for Cystic Fibrosis Clinical Research Proceedings of the ATS, August 1, 2007; 4(4): 399 - 405. [Abstract] [Full Text] [PDF]