Fixing cystic fibrosis CFTR with correctors and potentiators. Off to a good start

Since the cloning of the cystic fibrosis transmembrane regulator (CFTR) protein in the late 1980s and subsequent significant advances in understanding the pathophysiology of cystic fibrosis (CF) there have been high expectations that transformative, disease-modifying therapies could be developed.1 2 Dysfunction of the CFTR protein results in significant reduction or absence of chloride transport and dysregulation of sodium transport.3–5 Other cationic ions such as bicarbonate may also be transported by CFTR and the interaction with the epithelial sodium channel ENaC still remains to be elucidated.6 7 However, a significant number of in vitro and animal studies strongly support the premise that correction of CFTR function is possible and will make a significant impact on the CF phenotype, particularly in the lung, which accounts for most of the morbidity and mortality from this condition.7 Two approaches to correction of CFTR function are currently being pursued: one based on gene transfer therapy and the other on small molecule modulators. Gene therapy attempts to correct CFTR dysfunction in CF by transfection of airway cells with the wild-type CFTR gene to enable cells to express functional CFTR.8 Progress with this approach has been slow and methodical. Early studies suggest that it is possible to transfect nasal and bronchial epithelial cells and this results in a modest electrophysiological improvement.9 10 To date, there are no clinical studies in humans to determine if sufficient gene transfer can be achieved to result in a clinically meaningful benefit. A two-centre, double-blind, placebo-controlled trial of CF gene therapy is due to commence in the UK in 2012 using a specifically designed plasmid and a GL67 liposome complex. The results of this proof of concept study will help determine if gene therapy has the potential to provide a treatment which will benefit all mutation …