Elsevier

Clinical Biochemistry

Volume 45, Issue 15, October 2012, Pages 1132-1144
Clinical Biochemistry

Review
Cystic fibrosis: Insight into CFTR pathophysiology and pharmacotherapy

https://doi.org/10.1016/j.clinbiochem.2012.05.034Get rights and content

Abstract

Cystic fibrosis is the most common life-threatening recessively inherited disease in Caucasians. Due to early provision of care in specialized reference centers and more comprehensive care, survival has improved over time. Despite great advances in supportive care and in our understanding of its pathophysiology, there is still no cure for the disease. Therapeutic strategies aimed at rescuing the abnormal protein are either being sought after or under investigation. This review highlights salient insights into pathophysiology and candidate molecules suitable for CFTR pharmacotherapy. Clinical trials using Ataluren, VX-809 and ivacaftor have provided encouraging data. Preclinical data with inhibitors of phosphodiesterase type 5, such as sildenafil and analogs, have highlighted their potential for CFTR pharmacotherapy. Because sildenafil and analogs are in clinical use for other clinical applications, research on this class of drugs might speed up the development of new therapies for CF.

Graphical abstract

Highlights

► Despite great advances in supportive care, there is still no cure for CF. ► Therapeutic strategies aimed at rescuing the abnormal CFTR are under investigation. ► Clinical trials using Ataluren, VX-809 and ivacaftor have provided encouraging data. ► Preclinical data with sildenafil and analogs highlight their potential for CF therapy.

Introduction

Cystic fibrosis (CF) is the most common life-threatening recessively inherited disease in Caucasians. The disease is caused by genetic lesions in the CFTR (CF transmembrane conductance regulator) gene [1], [2] that encodes a protein that mainly functions as the most predominant chloride channel in exocrine epithelia. The basic defect in CF cells is the faulty chloride transport which causes dehydration of secretions with hyperviscous mucus and leads to chronic airway obstruction, pancreatic insufficiency and intestinal malabsorption. While many organs are affected in CF, pulmonary disease is the major cause of morbidity and mortality.

Approximately 80,000 people in the world are diagnosed with CF. However, CF shows wide geographic and ethnic variations, with prevalence ranging from 1 in 1700 to 7700 live births in Europe (the highest incidence is found in the Republic of Ireland while in Finland CF is extremely rare). CF is found to be rare in persons of non-Caucasian origin. The most prevalent CF-causing mutation in the Caucasian population, accounting for 86% of CF alleles (www.cftr2.org), is the F508del mutation, a deletion of the amino acid phenylalanine at position 508 of the encoded protein. Yet, presently over 1900 different CFTR mutations have been identified (www.genet.sickkids.on.ca).

Due to early referral to specialized, multidisciplinary reference centers for CF [3] and more comprehensive care, survival has improved over time. While in 1938, 70% of CF babies died within the first year of life [4], the median life expectancy of patients in the US reached 37 years in 2008 [5]. However, despite great advances in supportive care and in our understanding of pathophysiology of the disease, there is still no cure for CF.

Eighteenth century German and Swiss literatures warned: “Wehe dem Kind, das beim Kuß auf die Stirn salzig schmekt, es ist verhext und muss bald sterben”, which can be translated as: “Woe to that child which when kissed on the forehead tastes salty; he is bewitched and soon must die”. This adage is an early reference to the genetic disease recognized today as CF. The first clear description of CF was made in 1938 by Dorothy Andersen, a pathologist at the New York Babies Hospital; her paper entitled “Cystic fibrosis of the pancreas and its relation to celiac disease” [4] firmly established CF as a diagnosis separate and apart from celiac disease. Chronic respiratory infection was early recognized as one of the major symptoms and antibiotics were therefore introduced in the treatment of CF in the 1940s. When investigations evidenced that salty tasting skin occurs as a result of increased secretion of chloride and sodium by CF sweat glands, the use of the diagnostic pilocarpine sweat test was instigated in 1959 [6]. In the 1980s more knowledge on the underlying pathophysiology of the disease was brought about with the description of chloride impermeability of the CF sweat gland [7] and of altered chloride and sodium transport across CF respiratory epithelia [8]. The gene was cloned in 1989 [1], [2]. The subsequent decades have witnessed enormous progress toward understanding the molecular biology of the CFTR gene. The basic defect in CF was firmly established as a loss of function and/or expression of the CFTR protein. However the exact role of transepithelial ion transport in the pathogenesis of the disease is still not completely understood. Finding new medicines to fight CF and ultimately a cure has been the driving force of the Drug Development Pipeline of the CF Foundation (http://www.cff.org/research/DrugDevelopmentPipeline/). Despite the multimodal approach that has been adopted, CFTR modulation appears to be the most promising strategy. Present research is focusing on different pathophysiological aspects of the disease and on therapeutic strategies aimed at rescuing the abnormal protein. Currently, candidate molecules suitable for CFTR pharmacotherapy are either being sought after or under investigation. Based on the high prevalence of F508del-CFTR mutation, strategies to rescue the functional status of this particular mutant will benefit most of the CF population.

Section snippets

Structure and function of CFTR gene and protein

The CFTR gene is located in the long arm of chromosome 7 (7q31.2) [9], [10]. The encoded protein functions mainly as an adenosine 3′,5′-cyclic monophosphate (cAMP)-regulated chloride channel in a variety of polarized epithelia. The CF gene is large, spans approximately 250 kb, and contains 27 exons. The encoded mRNA is about 6.5 kb long and is translated into a protein product of 1480 amino acids. On the basis of the DNA sequence of the gene, a CFTR protein structure was postulated (Fig. 1). The

Pathophysiology of CFTR gene and protein

Under normal circumstances, the CFTR gene undergoes transcription and is translated into a CFTR protein that traffics to the cell membrane where it fully functions as a chloride channel (Fig. 2). In CF, the majority of CFTR mutations involve changes in three or fewer nucleotides and result in amino acid substitutions, frame shifts, splice site, or nonsense mutations. The most common and first identified mutation, the F508del, corresponds to a three base pair deletion that codes for

Clinical manifestations in CF

A simplified cascade of pathophysiology in CF lung disease is summarized in Fig. 4. CF respiratory phenotype is characterized by a vicious cycle of obstruction, inflammation and infection that progressively damages the airway tissue leading to respiratory failure and death. CF disease has a complex phenotype with variable disease severity and a broad clinical spectrum that reflects the underlying pathology of target organs and systems [73]. Clinically, typical or classical CF [74] is

Strategies for CF treatment

In recent years, growing efforts have been made to tailor interventional strategies that target the basic defects of CF rather than its symptoms. Following the discovery of the CF gene, some expectations arose that gene therapy, especially targeting topically the airways, would soon provide a treatment [100], [101]. In some trials, transgene expression has been detected, but no effective clinical benefit has thus far been recorded [102]. Access of the transfecting agents to the surface

Conclusion

Recent years have witnessed major advances in CF supportive care and in our understanding of CFTR pathophysiology. The basic defect in CF is reduced airway surface liquid volume related to faulty chloride and sodium transport across a variety of exocrine epithelia. Present research is focusing on the development of therapeutic strategies aimed at rescuing the abnormal protein that is either synthesized in reduced amounts or has poor anion conductance. Mutation-specific pharmacological

Acknowledgments

BL is a PhD fellow with the Fonds Spéciaux de Recherche (FSR; Académie Universitaire Louvain). SN is a postdoctoral researcher with the FSR and Marie Curie actions of the European Commission. TL is an associate researcher with the Fonds de la Recherche Scientifique Médicale (FRSM). This study was supported by the French CF Association, Vaincre la Mucoviscidose, the FSR and the Foundation St Luc (St Luc University Hospital and Université catholique de Louvain).

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    Authors' contributions: BL contributed to the work design, performed animal studies and helped in drafting the manuscript; BD contributed to the work design and helped in drafting the manuscript; SN contributed to the work design and helped in editing the manuscript; and TL designed and coordinated the work and edited the manuscript. All authors read and approved the final version of the manuscript.

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