CFTR Modulators: From Mechanism to Targeted Therapeutics

Yeh, Han-I; Sutcliffe, Katy J.; Sheppard, David N.; Hwang, Tzyh Chang

doi:10.1007/164_2022_597

Cited by 6 publications

(4 citation statements)

References 178 publications

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“…27 Thus, CFTR correctors increase the number of channels available to transport anions, while CFTR potentiators augment the activity of individual channels. 27 The combination of the correctors, elexacaftor, and tezacaftor, with the potentiator, ivacaftor (Trikfta ® /Kaftrio; VX-445-VX-661-VX-770; Vertex Pharmaceuticals, Boston, MA, USA) is a highly effective modulator therapy for people with CF heterozygous for F508del. Real-world data demonstrate convincingly that elexacaftor-tezacaftor-ivacaftor has exceptional health benefits for people with CF.…”

Section: Precision Medicine For Cystic Fibrosis: Matching Modulators ...mentioning

confidence: 99%

“…CFTR correctors overcome the misfolding and mis‐assembly of CFTR domains to permit the delivery of mutant CFTR protein to the plasma membrane, whereas CFTR potentiators enhance CFTR channel gating 27 . Thus, CFTR correctors increase the number of channels available to transport anions, while CFTR potentiators augment the activity of individual channels 27 . The combination of the correctors, elexacaftor, and tezacaftor, with the potentiator, ivacaftor (Trikfta ® /Kaftrio; VX‐445‐VX‐661‐VX‐770; Vertex Pharmaceuticals, Boston, MA, USA) is a highly effective modulator therapy for people with CF heterozygous for F508del.…”

Section: Introductionmentioning

confidence: 99%

“…Two types of modulators are currently licensed to treat CF. CFTR correctors overcome the misfolding and mis‐assembly of CFTR domains to permit the delivery of mutant CFTR protein to the plasma membrane, whereas CFTR potentiators enhance CFTR channel gating 27 . Thus, CFTR correctors increase the number of channels available to transport anions, while CFTR potentiators augment the activity of individual channels 27 .…”

Section: Introductionmentioning

confidence: 99%

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Experimental pharmacology in precision medicine

Urbaniak,

Thummel,

Alade

et al. 2023

Pharmacology Res & Perspec

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Section: Precision Medicine For Cystic Fibrosis: Matching Modulators ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Experimental pharmacology in precision medicine

Urbaniak,

Thummel,

Alade

et al. 2023

Pharmacology Res & Perspec

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“…Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed the treatment of the genetic disease cystic fibrosis (CF) (Heijerman et al., 2019; Middleton et al., 2019; Ramsey et al., 2011). These drugs target the root cause of CF, pathogenic variants in the epithelial anion channel CFTR, not just in the respiratory airways, the major site of disease, but in all affected organs (Ratjen et al., 2015; Yeh et al., 2022). Although most people with CF carry one or two copies of the predominant CFTR variant, c.1521_1523delCTT (p.Phe508del; legacy: F508del) (Cutting, 2015), over 2100 sequence variations have been reported in the CFTR gene (http://www.genet.sickkids.on.ca/), of which approximately 800 have been thoroughly vetted (https://cftr2.org/).…”

Section: Introductionmentioning

confidence: 99%

Two rare variants that affect the same amino acid in CFTR have distinct responses to ivacaftor

Li,

Rodrat,

Al‐Salmani

et al. 2024

The Journal of Physiology

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Some residues in the cystic fibrosis transmembrane conductance regulator (CFTR) channel are the site of more than one CFTR variant that cause cystic fibrosis. Here, we investigated the function of S1159F and S1159P, two variants associated with different clinical phenotypes, which affect the same pore‐lining residue in transmembrane segment 12 that are both strongly potentiated by ivacaftor when expressed in CFBE41o− bronchial epithelial cells. To study the single‐channel behaviour of CFTR, we applied the patch‐clamp technique to Chinese hamster ovary cells heterologously expressing CFTR variants incubated at 27°C to enhance channel residence at the plasma membrane. S1159F‐ and S1159P‐CFTR formed Cl− channels activated by cAMP‐dependent phosphorylation and gated by ATP that exhibited thermostability at 37°C. Both variants modestly reduced the single‐channel conductance of CFTR. By severely attenuating channel gating, S1159F‐ and S1159P‐CFTR reduced the open probability (Po) of wild‐type CFTR by ≥75% at ATP (1 mM); S1159F‐CFTR caused the greater decrease in Po consistent with its more severe clinical phenotype. Ivacaftor (10–100 nM) doubled the Po of both CFTR variants without restoring Po values to wild‐type levels, but concomitantly, ivacaftor decreased current flow through open channels. For S1159F‐CFTR, the reduction of current flow was marked at high (supersaturated) ivacaftor concentrations (0.5–1 μM) and voltage‐independent, identifying an additional detrimental action of elevated ivacaftor concentrations. In conclusion, S1159F and S1159P are gating variants, which also affect CFTR processing and conduction, but not stability, necessitating the use of combinations of CFTR modulators to optimally restore their channel activity. imageKey points Dysfunction of the ion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes the genetic disease cystic fibrosis (CF). This study investigated two rare pathogenic CFTR variants, S1159F and S1159P, which affect the same amino acid in CFTR, to understand the molecular basis of disease and response to the CFTR‐targeted therapy ivacaftor. Both rare variants diminished CFTR function by modestly reducing current flow through the channel and severely inhibiting ATP‐dependent channel gating with S1159F exerting the stronger adverse effect, which correlates with its association with more severe disease. Ivacaftor potentiated channel gating by both rare variants without restoring their activity to wild‐type levels, but concurrently reduced current flow through open channels, particularly those of S1159F‐CFTR. Our data demonstrate that S1159F and S1159P cause CFTR dysfunction by multiple mechanisms that require combinations of CFTR‐targeted therapies to fully restore channel function.

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