Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives

Figures & data

Figure 1 Pathophysiology of CF lung disease and potential therapies targeting the basic defect or the symptoms.

Note: In the absence of conclusive data on gene therapy, CFTR modulators are the most proximal therapy for CF currently in development.
Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium channel; mRNA, messenger RNA.

Figure 2 Predicted topology of CFTR protein.

Notes: It is composed of two repeated units made of a MSD followed by a NBD. The two repeated units are linked by a R domain. The MSDs consist of six hydrophobic transmembrane helices (or TMD). Several transmembrane helices contain one or more charged amino acids that control anion permeability. Extracellular loop 4 (between TMD7 and TMD8) contains two N-glycosylation sites.
Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; MSD, membrane-spanning domain; NBD, nucleotide-binding domain; TMD: transmembrane domain; R, regulatory domain.

Table 1 Classes of CFTR mutations

Class	Class I	Class II	Class III	Class IV	Class V	Class VI
Type of defect	No functional protein	Trafficking defect	Defective channel regulation	Decreased channel conductance	Reduced synthesis	Decreased stability
Examples of mutations	G542X	F508del	G551D	R117H	3849+10kbC→T	4326delTC
	W1282X	N1303K	G178R	R347P	2789+5G→A	Q1412X
	R553X	I507del	G551S	R117C	3120+1G→A	4279insA
	621+1G→T	R560T	S549N	R334W	5T

Abbreviation: CFTR, cystic fibrosis transmembrane conductance regulator.

Figure 3 Overview of the most advance CFTR modulators in preclinical and clinical studies, with regard to the class of CFTR mutations and the primary defect of the corresponding mutant protein.

Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; PTC, premature termination codon; EGCG, epigallocatechin gallate; ER, endoplasmic reticulum; Ub, ubiquitin; mRNA, messenger RNA.

Table 2 Mechanisms of action of pharmacological modulators of CFTR available to CF patients or under preclinical development as mono- and/or combitherapies for CF

Classes of compounds		Target	Mechanism of action	Pharmacological compounds
Monotherapies	PTC read-through	Class I (nonsense mutations)	Generate a full-length CFTR by complete translation of CFTR transcript	Ataluren Escin NB30, NB54, NB124
	mRNA repair therapy	All classes	Repair the CFTR mRNA to generate a WT-CFTR transcript	QR-010 (specific for F508del-CFTR)
	Correctors	Class II	Rescue F508del-CFTR to the plasma membrane	Lumacaftor, tezacaftor, VX-152, VX-440 Sildenafil, riociguat FDL-169 PTI-C1811
	Potentiators	Class III Class IV	Bind to CFTR to increase open probability	Ivacaftor CTP-656 QBW251 GLPG1837/ABBV-974 FDL-176
Combitherapies	Corrector/potentiator	Class II/III	Rescue F508del-CFTR to the plasma membrane, increase CFTR open probability	Lumacaftor/ivacaftor Tezacaftor/ivacaftor Lumacaftor/QBW251
	Corrector 1/corrector 2/potentiator	Class II/III	Rescue F508del-CFTR to the plasma membrane via two distinct mechanisms and increase CFTR open probability	Tezacaftor/VX-152/ivacaftor Tezacaftor/VX-440/ivacaftor
	Corrector/stabilizer	Class II	Rescue F508del-CFTR to the plasma membrane and enhance rescued F508del-CFTR stability	Cysteamine/EGCG
	Corrector/potentiator/stabilizer	Class II/III/VI	Rescue F508del-CFTR to the plasma membrane, increase CFTR open probability, and enhance rescued F508del-CFTR stability	Lumacaftor/ivacaftor/N91115
	Potentiator/stabilizer	Class VI	Increase CFTR open probability and enhance rescued F508del-CFTR stability	Ivacaftor/N91115
	Amplifier/other modulator(s)	All classes	Increase the amount of immature CFTR to provide more substrate for other modulators to act upon	PTI-428/other(s)

Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; CF, cystic fibrosis; PTC, premature termination codon; mRNA, messenger RNA; WT, wild type.