Chest
Volume 139, Issue 6, June 2011, Pages 1480-1490
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Recent Advances in Chest Medicine
Cystic Fibrosis Transmembrane Conductance Regulator Intracellular Processing, Trafficking, and Opportunities for Mutation-Specific Treatment

https://doi.org/10.1378/chest.10-2077Get rights and content

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?

Section snippets

CFTR Molecular Biology and Cellular Quality Control

The CFTR gene, comprising 180,000 base pairs, is located on the long arm of chromosome 7 and encodes a 1,480-amino acid membrane protein. The wild-type CFTR glycoprotein localizes in the apical plasma membrane and functions as a regulated chloride channel. CFTR might also affect bicarbonate-chloride exchange plus sodium and water transport in secretory and resorptive epithelium.3, 4 CFTR is a member of the large adenosine triphosphate (ATP)-binding cassette (ABC) transporter protein family. ABC

Correctors of Trafficking, Potentiators of Function, and Overcoming Premature Termination Codons

F508del, the missense mutation causing a phenylalanine deletion at position 508 in the CFTR protein, accounts for approximately 70% of all CF alleles and is found in up to 90% of patients with CF in some populations.45, 46 In addition to the high frequency of the F508del mutation, two other facts make corrective and potentiating therapies strategically relevant. First, F508del-CFTR retains function (albeit reduced relative to wild-type CFTR) when delivered to the apical plasma membrane.29, 47,

Five Classes of Defective CFTR Protein Processing Based on Gene Mutation

Although > 1,500 mutations of CFTR have been identified, only four specific mutations besides F508del reach a frequency of 1% to 3%: G551D, W1282X, G542X, and N1303K. In fact, only about 20 specific mutations reach a threshold frequency > 0.1% (Cystic Fibrosis Genetic Analysis Consortium database, www.genet.sickkids.on.ca/cftr). Specific mutations appear to be enriched within ethnic groups.53 For example, the nonsense mutation, W1282X (a PTC in place of tryptophan residue 1282) accounts for

Phenotypic Variation

When considering a uniformly homozygous F508del population, in general, the phenotype is severe, exhibiting pancreatic insufficiency and relentless progressive bronchiectasis. However, significant numbers of outliers with variable clinical severity exist. Variation can be attributed to the environment, the quantity of retained CFTR function, adherence to therapies, and genetic modifiers.63 Environmental variables include the advent of coordinated multidisciplinary CF care and enhanced mucous

Mutation Class and Prognostication

Certain generalizations about variable organ dysfunction traditionally have been linked to genotype severity. For example, almost all men with CF are infertile and, thus, the vas deferens generally are believed to be the most sensitive human organ to the CF genotype. Similarly, CF-related liver disease, exocrine pancreatic insufficiency, and malnutrition are more common in nonfunctional CFTR mutations. The pancreas, however, is somewhat less sensitive to loss of CFTR function. Individuals with

Progress Toward Mutation-Specific Modifier Treatments

Most of the current therapeutic strategies in use for CF involve treatments that alleviate symptoms and complications that result from loss of CFTR function, and consensus statements detailing these therapies have been published recently.68, 69 On the cutting edge of CF treatment, gene therapy continues to be pursued aggressively as evidenced by > 200 gene therapy trials undertaken since the 1990s. To date, effective and meaningful clinical outcomes remain elusive, and no gene therapies have

Concluding Perspectives

Mutation-specific treatments hold promise for finally answering 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? The successes reported from early phase trials translating mutation-specific approaches into measurable patient outcomes have created much excitement, and

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Hornick has participated in enrolling patients in early phase clinical trials of Vertex Pharmaceuticals products and has participated in the writing of manuscripts and abstracts describing results of studies. Drs Rogan and Stoltz have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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    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).

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