An Introduction to Clinical Aspects of Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is the most common life shortening inherited disease in people of Northern European background. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is a 1480 base protein belonging to the ABC transporter family. It acts as a cAMP-activated chloride and bicarbonate channel and also regulates Na reabsorption through its effect on the epithelial sodium channel (ENaC). The loss of CFTR-mediated inhibition of ENaC leads to excess sodium and water reabsorption, resulting in dehydration of airway surface materials, and dehydration of airway surface materials. Concomitant loss of chloride efflux prevents the epithelium from correcting the low airway surface water volume. The subsequent decrease in periciliary water volume results in a reduction in the lubricating layer between the epithelium and mucus, causing inhibition of normal ciliary clearance of mucus. In addition to abnormalities in ion transport, dysregulation of the host inflammatory response appears to play an important role in cystic fibrosis. It is characteristic of CF that the airways become infected with pathogenic bacteria. Compounding the inability to clear infection, patients with CF also exhibit abnormal inflammatory signaling and an excessive inflammatory response. With persistent infection and periodic exacerbations of the chronic infection, progressive lung disease develops. Thus, in spite of the progress in treatment that has been made, the overwhelming majority of patients still die from respiratory failure. Treatment has traditionally focused on the downstream effects of CFTR dysfunction, and includes therapies that correct altered airway secretions (physical airway clearance therapy, dornase alfa, hypertonic saline, and the recently approved inhaled mannitol); anti-inflammatory therapies (high-dose ibuprofen and alternate-day azithromycin); anti-infective therapies (inhaled anti-pseudomonal antibiotics such as tobramycin and aztreonam, along with intermittent treatment with systemic antibiotics of episodic pulmonary exacerbations), and when lung damage is severe, lung transplantation. The recent development of first generation CFTR modulating agents to treat CFTR dysfunction (ivacaftor, a potentiator that activates defective CFTR at the cell surface, and lumacaftor, a CFTR corrector that facilitates transport of class II mutations to the apical cell surface) marks the beginning of a new era of mutation-specific therapies to improve the function of defective CFTR protein. A number of next-generation modulators and other agents are currently moving through the drug development pipeline, offering hope for increased optimism regarding continuing improvements in the long-term outlook of this difficult disease.