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Recent Advances in Chest Medicine |

Cystic Fibrosis Transmembrane Conductance Regulator Intracellular Processing, Trafficking, and Opportunities for Mutation-Specific Treatment

Mark P. Rogan, MD; David A. Stoltz, MD, PhD; Douglas B. Hornick, MD, FCCP
Author and Funding Information

From the Department of Respiratory Medicine (Dr Rogan), Waterford Regional Hospital, Waterford, Ireland; and Department of Internal Medicine (Drs Stoltz and Hornick), Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA.

Correspondence to: Douglas B. Hornick, MD, FCCP, Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Internal Medicine, C-33 GH UIHC, 200 Hawkins Dr, Iowa City, IA 52242; e-mail: douglas-hornick@uiowa.edu


Funding/Support: Dr Hornick is supported in part by the Cystic Fibrosis Foundation Translational Center Grant, which included funding to participate in industry-sponsored (eg, PTC Therapeutics, Vertex Pharmaceuticals) clinical trials.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(6):1480-1490. doi:10.1378/chest.10-2077
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Recent advances in basic science have greatly expanded our understanding of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), the chloride and bicarbonate channel that is encoded by the gene, which is mutated in patients with CF. We review the structure, function, biosynthetic processing, and intracellular trafficking of CFTR and discuss the five classes of mutations and their impact on the CF phenotype. The therapeutic discussion is focused on the significant progress toward CFTR mutation-specific therapies. We review the results of encouraging clinical trials examining orally administered therapeutics, including agents that promote read-through of class I mutations (premature termination codons); correctors, which overcome the CFTR misfolding that characterizes the common class II mutation F508del; and potentiators, which enhance the function of class III or IV mutated CFTR at the plasma membrane. Long-term outcomes from successful mutation-specific treatments could finally answer the question that has been lingering since and even before the CFTR gene discovery: Will therapies that specifically restore CFTR-mediated chloride secretion slow or arrest the deleterious cascade of events leading to chronic infection, bronchiectasis, and end-stage lung disease?

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