Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies

Abstract

Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in epithelial cells throughout the body. In the lungs, absence or dysfunction of CFTR results in altered epithelial salt and water transport eventuating in impaired mucociliary clearance, chronic infection and inflammation, and tissue damage. CF lung disease is the major cause of morbidity and mortality in CF despite the many therapies aimed at reducing it. However, recent technological advances combined with two decades of research driven by the discovery of the CFTR gene have resulted in the development and clinical testing of novel therapies aimed at the principal underlying defect in CF, thereby ushering in a new age of therapy for CF.

Figure 1. CFTR model

The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette family of proteins. It consists of 7 domains: intracellular amino and carboxy terminal domains, 2 6-segment membrane-spanning domains, a regulatory R-domain, and 2 nucleotide-binding domains.

Figure 2. The vicious cycle of CF lung disease

Figure 3. Depletion of airway surface liquid in CF

In vitro and in vivo evidence supports the hypothesis that absence or dysfunction of CFTR in the airways results in hyperabsorption of sodium from the airway surface liquid. This results in osmotic absorption of water, causing depletion of the airway surface liquid. Depletion of airway surface liquid prevents normal ciliary beating, resulting in mucus retention.

Figure 4. Novel CFTR-directed therapies

Three novel types of CFTR-directed therapies are currently being investigated. A. For class I mutations resulting in premature termination of translation, there are promoters of ribosomal read-through such as PTC124. B. For class II mutations, including ΔF508 CFTR, that cause abnormal protein folding and trafficking, there are small molecule correctors, such as VX-809, that increase surface expression of the mutant protein that retains some function as a chloride channel. C. For class III mutations such as G551D CFTR that have abnormal channel regulation, there are potentiators, such as VX-770, that increase the chloride conductance of the abnormal channel in the apical plasma membrane (Van Goor et al., 2009). VX-770 is also currently in clinical trials in patients with ΔF508 CFTR to investigate whether it will potentiate the function of any mutant CFTR that reaches the apical plasma membrane.