Cystic Fibrosis: Emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications

Abstract

Cystic fibrosis (CF) remains the most common life-shortening hereditary disease in white populations, with high morbidity and mortality related to chronic airway mucus obstruction, inflammation, infection, and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that encodes a cAMP-dependent anion channel vital for proper Cl^- and HCO₃^- transport across epithelial surfaces provided a solid foundation for unraveling underlying disease mechanisms and the development of therapeutics targeting the basic defect in people with CF. In this review, we focus on recent advances in our understanding of the molecular defects caused by different classes of CFTR mutations, implications for pharmacological rescue of mutant CFTR, and insights into how CFTR dysfunction impairs key host defense mechanisms, such as mucociliary clearance and bacterial killing in CF airways. Furthermore, we review the path that led to the recent breakthrough in the development of highly effective CFTR-directed therapeutics, now applicable for up to 90% of people with CF who carry responsive CFTR mutations, including those with just a single copy of the most common F508del mutation. Finally, we discuss the remaining challenges and strategies to develop highly effective targeted therapies for all patients and the unprecedented potential of these novel therapies to transform CF from a fatal to a treatable chronic condition.

Keywords: CF pathogenesis; CFTR mutations; clinical trials; personalized medicine; targeted therapies.

Figure 1.

Role of CFTR in healthy airways and molecular mechanisms causing CFTR dysfunction in cystic fibrosis airways. (A) In healthy airways, CFTR is expressed at the apical surface of airway epithelial cells together with the epithelial Na⁺ channel ENaC. CFTR plays a central role in cAMP-mediated anion (Cl⁻ and HCO₃⁻) 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 cystic fibrosis (CF), a spectrum of CFTR mutations causes CFTR dysfunction via different molecular mechanisms. (B) CFTR nonsense, frameshift, or canonical splicing mutations (class I) abrogate CFTR synthesis. (C) Many missense mutations, including the most common F508del mutation, impair CFTR folding (class II) and lead to retention in the endoplasmic reticulum and degradation by the proteasome. (D) Some missense and noncanonical splicing mutations produce CFTR anion channels that reach the cell surface but are not fully functional because of a spectrum of defects, such as altered regulation reducing their 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. Adapted by permission from Reference .

Figure 2.

Schematic of approach to CFTR restoration with small molecules, by mutation class. Therapeutic approaches with definitive studies in solid boxes; those under investigation with dashed boxes. CFTR mutations can be addressed pharmacologically based on their underlying molecular defect. Nonsense mutations, a form of class I mutation, have the potential to be restored by premature termination codon (PTC)-suppressing drugs that induce full-length functional CFTR protein. As some protein forms generated by translational readthrough are dysfunctional, the addition of correctors and/or potentiators may also be needed. Misfolded mutations including Phe508del require multiagent therapy to first restore processing and trafficking with one or two CFTR correctors, then augmentation of ion channel function by CFTR potentiators. Mutations that are localized to the cell surface but are dysfunctional, as in class III, IV, and V mutations, can be addressed by CFTR potentiators alone. Class VI mutations, not shown, are expected to behave similarly. CFTR amplifiers that increase CFTR transcription and/or translation efficiency would also be expected to have broad ranging effects across mutation classes once efficacy is established. UGA = urinidine-guanosine-adenosine ‘opal’ stop codon. Illustration by Patricia Ferrer Beals. Adapted by permission from Reference .

Figure 3.

Clinical benchmarks for CFTR modulation. (A) Clinical improvement by change in FEV₁ percent predicted versus placebo at the time of the primary endpoint is plotted for each of the phase 3 trials when available (or phase 2 trials when drug development was halted) in the populations shown. Tezacaftor (TEZ)/ivacaftor (IVA) in F508del (F)/residual function mutation (RF) may approach the highly effective benchmark for many patients, as baseline CFTR activity is higher in that group, by definition. (B) CFTR activity measured in vitro using primary human bronchial epithelial cells on stimulation with CFTR agonists, and estimated as a proportion of wild-type (WT) CFTR activity based on published data, are plotted compared with the change in FEV₁ percent predicted for the groups shown in A. WT CFTR activity is estimated from donors without cystic fibrosis and can vary over time. Data are determined from references or public presentations (92, 102, 110, 111, 169, 178, 179) and adapted and updated from a prior review (180). The effect of elexacaftor (ELX)/TEZ/IVA in patients homozygous for F508del includes the added effects of TEZ/IVA and the subsequent addition of ELX to that population. G = G551D; LUM = lumacaftor; MF = minimal function mutation.

Figure 4.

Trial design issues across a transitional cystic fibrosis population with access to highly effective CFTR modulator therapy (HEMT). SOC = standard of care. Illustration by Patricia Ferrer Beals.