CF transmembrane conductance regulator (CFTR) modulators in cystic fibrosis (CF)

Last edited 06/2021 and last reviewed 06/2021

Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these

• although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients
• life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens

Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations

• in this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators
• modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations:
  • potentiators
    • around 5% of CF-causing mutations lead to impaired CFTR channel gating or conductance as primary defects (Classes III and IV)
      • the R117H, R334W, R347P, and G551D are among the most common mutations that cause such abnormalities and they are found in 1.3%, 0.3%, 0.4%, and 2.1% of CF alleles, respectively
    • potentiators are compounds that restore or even enhance the channel open probability, thus allowing for CFTR-dependent anion conductance
      
      
  • correctors
    • most CF patients carry a mistrafficking CFTR mutation, since F508del is the most prevalent CF-causing mutation (Class II)
      • other common mutations that cause such abnormality are the G85E, I507del, R560T, and N1303K (found in 0.4%, 0.5%, 0.2%, and 1.6% CF alleles, respectively)
    • correctors are compounds that rescue folding, processing and trafficking to the PM of a CFTR mutant
      • while these compounds may act by distinct mechanisms, they usually enhance protein conformational stability during the ER folding process
        
        
  • stabilizers
    • although certain CFTR mutants are functional and present at the plasma membrane (PM), the protein may still display a significant reduction in half-life (Class VI), probably due to accelerated endocytosis and/or reduced recycling
      • low temperature incubation rescues CFTR in F508del-expressing cells (r.F508del), but the protein still demonstrates reduced stability and is rapidly removed by peripheral quality control mechanisms
      • in fact, environmental stresses may also lead to destabilization and internalization of WT-CFTR
    • stabilizers are agents that anchor CFTR at the PM, thus preventing its removal and degradation by lysosomes
      
      
  • read-through agents
    • a significant fraction of the CF-causing mutations are in-frame nonsense, frameshift, and splicing variants that introduce a premature termination codon (PTC) into the CFTR mRNA, thus abrogating CFTR protein synthesis or resulting in translation of shortened, truncated forms (Class I)
    • PTCs are also subjected to nonsense-mediated mRNA decay (NMD), resulting in substantial decrease in the quantity of CFTR transcripts
      • around 10% of CF patients worldwide carry a PTC mutation, with G542X and W1282X being the most common PTC variants found in CF alleles (2.5% and 1.2%, respectively)
    • read-through agents are compounds that induce a ribosomal "over-reading" of a PTC, enabling the incorporation of a foreign amino acid in that place and thus the continued translation to the normal end of the transcript
      
      
  • amplifiers
    • some CF-causing mutations lead to reduction in the synthesis or maturation of CFTR protein
      • the 3849+10kbC>T, 2789+5G>A, and A455E are common mutations that cause such abnormalities (Class V) and are found in 0.8%, 0.7%, and 0.4% of the CF alleles, respectively
      • amplifiers are compounds that increase expression of CFTR mRNA and, consequently, biosynthesis of the CFTR protein

Reference:

• Lopes-Pacheco M. CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicin. Front Pharmacol. 2019; 10: 1662.