Review
A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect

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Summary

Cystic fibrosis is caused by dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial chloride channel that has a key role in maintaining homoeostasis of the airway surface liquid layer in the lungs. More than 1900 CFTR mutations that might result in a disease phenotype have been identified; these can be grouped into classes on the basis of their effect on CFTR protein production, trafficking, function, and stability. In the past 2 years, landmark clinical trials have shown that correction of CFTR function leads to substantial clinical benefit for individuals with cystic fibrosis. These findings are ushering in a new era of cystic fibrosis treatments designed to correct the underlying CFTR defect caused by different mutation classes. With analysis of continuing trials and available patient registries, here we assess mutation types and the number and geographical distribution of patients who are likely to benefit from CFTR-correcting treatment.

Introduction

Cystic fibrosis transmembrane conductance regulator (CFTR) protein is found in the apical plasma membrane of airway, intestinal, and exocrine epithelial cells. One of CFTR's primary roles in the lungs is to maintain homoeostasis of the airway surface liquid layer through its function as a chloride channel and its regulation of the epithelial sodium channel ENaC.1 This liquid layer lines the airways and allows cilia to protect the lungs through continuous mucociliary clearance. If an individual has genetic mutations that cause CFTR dysfunction, the CFTR chloride channel does not work correctly and ENaC is not appropriately regulated, resulting in increased fluid and sodium resorption from the airways and formation of a contracted viscous surface liquid layer.1, 2 This abnormality, defects in the innate lung defence,3 and an intrinsic pro-inflammatory status,4 form the basis for cystic fibrosis lung pathology,5 which results in a progressive cycle of lung damage from recurrent mucous plugging, infection, and inflammation.

For the past 50 years, nearly all new pulmonary treatments for cystic fibrosis have targeted one of two characteristic components of the disease: viscous mucus or chronic airway infection. The hope was that if these components were addressed, the progressive cycle of airway obstruction, inflammation, and lung damage could be interrupted. Discussions since the discovery of the cystic fibrosis gene in 19896 of potential strategies to address the underlying chloride channel defect characteristic of cystic fibrosis have been frequent but have remained theoretical.7, 8 However, the results of a 2011 landmark phase 3 study of individuals with the Gly551Asp mutation showed that correction of the underlying channel defect of CFTR is possible and has clinical benefit in individuals with cystic fibrosis.9 These results signal a new era in treatment of the disease, in which patient outcomes will be improved by correction of the underlying chloride channel defect. This advancement would represent a triumph of so-called bench-to-bedside medicine and lay a path for treatment of other genetic illnesses. However, to understand how these new treatments will work and what subsets of patients with cystic fibrosis are most likely to benefit, CFTR mutations and their effect on CFTR function must be understood.

Section snippets

CFTR mutation classes

More than 1900 CFTR mutations that might cause dysfunction of the CFTR protein and result in a cystic fibrosis phenotype have been identified. The disease has a classic recessive inheritance pattern; ie, an individual must have a pathological CFTR mutation on each chromosome to develop the disease phenotype. CFTR mutations can be grouped into six classes on the basis of their effect on CFTR protein production, trafficking, function, or stability (figure 1).10 Class I mutations result in no

Treatments to correct the basic CFTR defect

To understand emerging treatments designed to correct the basic CFTR defect, the mechanisms of CFTR dysfunction in the different mutation classes need to be understood. The underlying CFTR difficulties in some CFTR mutations will be harder to address than others—particularly class I and II mutations in which little or no CFTR is present at the cell surface. Encouragingly, all six classes presently have emerging treatments or clinical trials in progress or both, with potential to address the

Patient populations likely to benefit from CFTR-correcting treatment

Examination of presently available patient databases allows a more accurate assessment of the number and geographical distribution of patients likely to benefit from CFTR-correcting treatment. These databases show striking heterogeneity between countries in the frequency of specific CFTR mutations. In total, Gly551Asp is found in 3–4% individuals with cystic fibrosis; the mutation is rare in some countries, but in others such as Ireland, Australia, and the UK, prevalence is as high as 14%, 8%,

Conclusions

Therapeutic developments suggest that the next few years will be a more exciting time for cystic fibrosis treatments than any other in history. A growing number of patients with cystic fibrosis are likely to benefit from the CFTR potentiator ivacaftor, and a substantially larger number will benefit if corrector treatment is found to be efficacious in patients with Phe508del. This focus on correction of the underlying CFTR defect will reshape the approach to treatment of cystic fibrosis and

Search strategy and selection criteria

We searched PubMed for articles published between Jan 1, 1971, and Aug 31, 2012, with the terms “cystic fibrosis”, “CFTR mutation class”, and “cystic fibrosis drug therapy”. We searched ClinicalTrials.gov with the term “cystic fibrosis”. We included articles published in English, French, and German.

This publication has been corrected. The corrected version first appeared at thelancet.com/respiratory on April 5, 2013

References (35)

  • PA Flume et al.

    Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation

    Chest

    (2012)
  • JL Mendoza et al.

    Requirements for efficient correction of DeltaF508 CFTR revealed by analyses of evolved sequences

    Cell

    (2012)
  • K De Boeck et al.

    Guideline on the design and conduct of cystic fibrosis clinical trials: the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN)

    J Cyst Fibros

    (2011)
  • P Moskwa et al.

    A novel host defense system of airways is defective in cystic fibrosis

    Am J Respir Crit Care Med

    (2007)
  • RC Boucher

    Evidence for airway surface dehydration as the initiating event in CF airway disease

    J Intern Med

    (2007)
  • B Kerem et al.

    Identification of the cystic fibrosis gene: genetic analysis

    Science

    (1989)
  • BW Ramsey et al.

    A CFTR potentiator in patients with cystic fibrosis and the G551D mutation

    N Engl J Med

    (2011)
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