Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Abstract

Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation

“…This suggests that measurement of sweat chloride levels may not be sufficient to provide reassurance of the clinical efficacy of treatment. Nevertheless, although the findings suggest that sweat chloride concentrations cannot predict treatment efficacy, the ''sweat test'' may still be useful in determining response to treatment [7].…”

“…As already discussed by DERICHS [7], volume depletion of the lung airway surface liquid is caused by a reduction in the quantity or activity of CFTR protein in the apical membrane of lung epithelial cells [4]. Accumulation of thickened mucus inevitably leads to impaired mucociliary transport, mucus stasis, airway obstruction and pathogen-induced inflammation.…”

“…Ivacaftor was discovered using high-throughput screening of cell-culture systems recombinantly expressing G551D-CFTR. The candidate was validated using follow-up in vitro analyses (refer to [7]) before rapidly advancing into clinical trials.…”

MANAGEMENT OF ENDOCRINE DISEASE: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues

“…Novel therapeutics approaches have been recently used in connection with a better understanding of CFTR pathophysiology, including the development of 'transformational' or 'modulatory' drugs aiming to restore CFTR functions (51). Despite the recent arrival of these promising novel drugs to the clinical arena, its use is so far limited.…”

Personalised medicine for cystic fibrosis: treating the basic defect

“…DERICHS [17] will provide an overview of the genetics and pathophysiology of CF and how this knowledge is being applied to CF drug discovery. He will also comment on the various classes of CFTR mutations and how they can be targeted by CFTR modulators, as well as briefly examining the proposed mechanisms of action of CFTR modulators before focusing on the pre-clinical development of ivacaftor.…”