**2. The pathophysiology of cystic fibrosis**

Cystic fibrosis is the direct result of a mutation in both alleles of *CFTR*. This gene is responsible for encoding the CFTR protein, a chloride ion channel anchored in the plasma membrane of lung cells, pancreatic cells, sweat and other exocrine glands. Functionally, CFTR is important for the production and movement of sweat, digestive fluids, and mucus across the membrane, where mutations in the encoding gene may result in impaired anion secretion and hyperabsorption of sodium across epithelia [4–6].

Over 1500 different mutations have been described in the CFTR gene, each leading to different defects in the CFTR protein itself [7]. In the most common mutation, the deletion of phenyla‐ lanine (F) from position 508 (∆F508), improper protein folding results in the degradation of CFTR by the cell, which limits the amount of CFTR that reaches the epithelial cell surface. ∆F508-CFTR accounts for approximately 70% of CF cases worldwide and 90% of those occurring in the United States [7].

Alternative mutations in CFTR may result in truncation of the protein via premature stop codons, prevention of proper processing, folding, or trafficking to the plasma membrane, or interference with the chloride channel's ion transport ability, leading to poor gating or conductance [8]. A patient's specific CFTR gene mutation often dictates the severity of his or her disease, as well as the availability of drugs designed to target their particular protein defect.

In addition to mutations within *CFTR* itself, polymorphisms in other genes may also modify disease severity in patients with CF [9,10]. For instance, genetic variation in the gene encoding transforming growth factor β1 (*TGFβ1*) has been associated with more severe pulmonary phenotypes predictive of poorer long-term outcomes [9]. Polymorphisms in the histone-deacetylase-dependent transcriptional co-regulator, *IFRD1*, have also been shown to modulate the pathogenesis of CF lung disease through the regulation of neutrophil effector function [10,11].

Traditional management strategies for CF typically involve the use of antibiotics to treat infection as well as agents or mechanical devices to improve mucus clearance and prevent damage to the lungs. Non-CFTR ion channel agents, for instance, are small molecules designed to normalize the transport of sodium and chloride by targeting non-CFTR ion channels expressed by epithelial cells. Osmotic agents, or inhaled hypertonic solutions, have also been employed to restore airway surface liquid by drawing liquid out of the airway epithelium and into the mucus [12].

In more recent years, the characterization of *CFTR* mutations and genetic modifiers have provided numerous targets for the development of novel therapies aimed at treating the underlying cause, rather than symptoms, of the disease. These agents are designed to directly compensate for *CFTR* mutations in one of three main ways:


and 1 out of every 2,000–3,000 in the European Union, CF affects more than 70,000 individuals worldwide [2]. Chronic lung disease is the major factor contributing to morbidity and mortality among CF patients, as abnormal airway secretions and chronic endobronchial infection lead to progressive airway obstruction. In addition to the respiratory tract, the disease may also

Disease severity varies greatly among those with CF, depending largely upon the degree to which the lungs are affected. However, eventual deterioration of the lungs leading to airway obstruction and death is inevitable, and for many years the average CF patient was not expected to reach adulthood [2]. Over the course of the past three decades, advancements in modern medicine have allowed physicians to postpone debilitating changes to the lungs, slowing the progression of disease and allowing many individuals with CF to live well into their 50s or 60s. Despite these advances in current therapy, the median age of survival remains only 33.4 years [2], emphasizing the need for novel therapeutic approaches to further improve

Cystic fibrosis is the direct result of a mutation in both alleles of *CFTR*. This gene is responsible for encoding the CFTR protein, a chloride ion channel anchored in the plasma membrane of lung cells, pancreatic cells, sweat and other exocrine glands. Functionally, CFTR is important for the production and movement of sweat, digestive fluids, and mucus across the membrane, where mutations in the encoding gene may result in impaired anion secretion and hyper-

Over 1500 different mutations have been described in the CFTR gene, each leading to different defects in the CFTR protein itself [7]. In the most common mutation, the deletion of phenyla‐ lanine (F) from position 508 (∆F508), improper protein folding results in the degradation of CFTR by the cell, which limits the amount of CFTR that reaches the epithelial cell surface. ∆F508-CFTR accounts for approximately 70% of CF cases worldwide and 90% of those

Alternative mutations in CFTR may result in truncation of the protein via premature stop codons, prevention of proper processing, folding, or trafficking to the plasma membrane, or interference with the chloride channel's ion transport ability, leading to poor gating or conductance [8]. A patient's specific CFTR gene mutation often dictates the severity of his or her disease, as well as the availability of drugs designed to target their particular protein defect. In addition to mutations within *CFTR* itself, polymorphisms in other genes may also modify disease severity in patients with CF [9,10]. For instance, genetic variation in the gene encoding transforming growth factor β1 (*TGFβ1*) has been associated with more severe pulmonary phenotypes predictive of poorer long-term outcomes [9]. Polymorphisms in the histone-deacetylase-dependent transcriptional co-regulator, *IFRD1*, have also been shown to modulate the pathogenesis of CF lung disease through the regulation of neutrophil

affect the pancreas, liver, kidneys, intestine, and reproductive system [3].

patient outcomes in CF.

358 Cystic Fibrosis in the Light of New Research

**2. The pathophysiology of cystic fibrosis**

absorption of sodium across epithelia [4–6].

occurring in the United States [7].

effector function [10,11].
