CFTR modulator therapy for cystic fibrosis caused by the rare c.3700A>G mutation

• Published in: Journal of cystic fibrosis Vol. 20; no. 3; pp. 452 - 459
• Main Authors: Phuan, Puay-Wah, Haggie, Peter M., Tan, Joseph A., Rivera, Amber A., Finkbeiner, Walter E., Nielson, Dennis W., Thomas, Merlin M., Janahi, Ibrahim A., Verkman, Alan S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2021
• Subjects: Aminophenols; Aminopyridines; Benzodioxoles; C.3700A>G; Cells, Cultured; CFTR modulators; Chloride Channel Agonists - pharmacology; Co-potentiators; Cystic fibrosis; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Humans; I1234V; Indoles; Mutant Proteins - drug effects; Mutation, Missense; N-of-1 clinical trials; Pulmonary/Respiratory; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; I1234V; N-of-1 clinical trials; Cystic fibrosis; C.3700A>G; Co-potentiators; CFTR modulators
• ISSN: 1569-1993; 1873-5010; 1873-5010
• DOI: 10.1016/j.jcf.2020.07.003

•The c.3700A>G mutation in the CFTR gene produces two protein products, one with single missense mutation (I1234V-CFTR) and a second with six amino acids deleted from nucleotide binding domain 2 (p.Ile1234_Arg1239del-CFTR, I1234del-CFTR).•I1234V-CFTR function is similar to that of wild type CFTR, whereas I1234del-CFTR is impaired in its cellular processing and channel gating.•I1234del-CFTR is responsive to approved CFTR modulator drugs, including VX-445, VX-661, VX-809 and VX-770.•I1234del-CFTR can be activated by investigational CFTR modulators, including co-potentiators and mutation-specific correctors.•Trikafta therapy in two c.3700A>G homozygous cystic fibrosis subjects showed modest clinical benefit. The c.3700A>G mutation, a rare cystic fibrosis (CF)-causing CFTR mutation found mainly in the Middle East, produces full-length transcript encoding a missense mutation (I1234V-CFTR), and a cryptic splice site that deletes 6 amino acids in nucleotide binding domain 2 (I1234del-CFTR). FRT cell models expressing I1234V-CFTR and I1234del-CFTR were generated. We also studied an I1234del-CFTR-expressing gene-edited human bronchial (16HBE14o-) cell model, and primary cultures of nasal epithelial cells from a c.3700A>G homozygous subject. To identify improved mutation-specific CFTR modulators, high-throughput screening was done using I1234del-CFTR-expressing FRT cells. Motivated by the in vitro findings, Trikafta was tested in two c.3700A>G homozygous CF subjects. FRT cells expressing full-length I1234V-CFTR had similar function to that of wildtype CFTR. I1234del-CFTR showed reduced activity, with modest activation seen with potentiators VX-770 and GLPG1837, correctors VX-809, VX-661 and VX-445, and low-temperature incubation. Screening identified novel arylsulfonyl-piperazine and spiropiperidine-quinazolinone correctors, which when used in combination with VX-445 increased current ~2-fold compared with the VX-661/VX-445 combination. The combination of VX-770 with arylsulfonamide-pyrrolopyridine, piperidine-pyridoindole or pyrazolo-quinoline potentiators gave 2–4-fold greater current than VX-770 alone. Combination potentiator (co-potentiator) efficacy was also seen in gene-edited I1234del-CFTR-expressing human bronchial epithelial cells. In two CF subjects homozygous for the c.3700A>G mutation, one subject had a 27 mmol/L decrease in sweat chloride and symptomatic improvement on Trikafta, and a second subject showed a small improvement in lung function. These results support the potential benefit of CFTR modulators, including co-potentiators, for CF caused by the c.3700A>G mutation.