Ion Channel Modulators in Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains one of the most common life-shortening genetic diseases affecting the lung and other organs. CFTR functions as a cyclic adenosine monophosphate-dependent anion channel that transports chloride and bicarbonate across epithelial surfaces, and disruption of these ion transport processes plays a central role in the pathogenesis of CF. These findings provided the rationale for pharmacologic modulation of ion transport, either by targeting mutant CFTR or alternative ion channels that can compensate for CFTR dysfunction, as a promising therapeutic approach. High-throughput screening has supported the development of CFTR modulator compounds. CFTR correctors are designed to improve defective protein processing, trafficking, and cell surface expression, whereas potentiators increase the activity of mutant CFTR at the cell surface. The approval of the first potentiator ivacaftor for the treatment of patients with specific CFTR mutations and, more recently, the corrector lumacaftor in combination with ivacaftor for patients homozygous for the common F508del mutation, were major breakthroughs on the path to causal therapies for all patients with CF. The present review focuses on recent developments and remaining challenges of CFTR-directed therapies, as well as modulators of other ion channels such as alternative chloride channels and the epithelial sodium channel as additional targets in CF lung disease. We further discuss how patient-derived precision medicine models may aid the translation of emerging next-generation ion channel modulators from the laboratory to the clinic and tailor their use for optimal therapeutic benefits in individual patients with CF.

Keywords: cystic fibrosis; pharmacotherapy; translating basic research.

Figure 1

A-D, Role of CFTR in healthy airways and molecular mechanisms causing CFTR dysfunction in cystic fibrosis (CF). A, In healthy airways, CFTR is expressed at the apical surface of airway epithelial cells together with the ENaC. CFTR plays a central role in cyclic adenosine monophosphate-mediated anion (chloride and bicarbonate) and fluid secretion, and ENaC is limiting for the absorption of sodium and fluid across the airway epithelium. Coordinated regulation of CFTR and ENaC enables proper airway surface hydration and effective mucociliary clearance. B-D, In CF, different mutations in CFTR cause CFTR dysfunction via different molecular mechanisms. B, CFTR nonsense or splicing mutations (class I) abrogate CFTR production. C, Many missense mutations, including the common F508del mutation, impair proper folding (class II) of CFTR and lead to retention in the endoplasmic reticulum and degradation by the proteasome. D, Some missense and splicing mutations produce CFTR chloride channels that reach the cell surface but are not fully functional due to a spectrum of defects such as altered regulation reducing the open probability (class III), diminished ion conductance (class IV), reduced amount of functional CFTR (class V), or decreased membrane residence time of CFTR at the apical surface (class VI). A common consequence of CFTR dysfunction and unbalanced ENaC-mediated sodium/fluid absorption is airway surface dehydration and impaired mucociliary clearance setting the stage for airway mucus plugging, chronic infection, and inflammation in patients with CF. CFTR = cystic fibrosis transmembrane conductance regulator; ENaC = epithelial sodium channel.

Figure 2

Ion channel modulation in CF. A-D, Current pharmacologic approaches to restore CFTR function and improve airway surface hydration in CF airways. A, CFTR potentiator compounds (green) activate mutant CFTR chloride channels that are expressed at the apical cell membrane and show impaired channel gating such as the G551D mutation, or have reduced ion conductance such as R117H. B, CFTR corrector compounds (red) facilitate transfer of misfolded F508del-CFTR to the apical cell membrane, where it can be further activated by a potentiator compound providing the rationale for corrector-potentiator combination therapies. C-D, ENaC blockers (yellow) inhibit ENaC-mediated absorption of sodium and fluid from airway surfaces. This approach improves airway surface hydration even in the absence of functional CFTR (C) and may augment benefits of partial rescue of CFTR mutants by current CFTR modulator therapies (D). Alternative chloride channels such as transmembrane protein member 16A and SLC26A9 constitute additional therapeutic targets to compensate for deficient CFTR-mediated anion secretion in CF (not shown). See Figure 1 legend for expansion of other abbreviations.