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

Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society
Puay-Wah PhuanAlan S Verkman

Abstract

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. T...Continue Reading

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Citations

May 1, 2021·International Journal of Molecular Sciences·Duncan E Keegan, John J Brewington
Jun 3, 2021·Journal of Personalized Medicine·Simon Y GraeberMarcus A Mall
Aug 7, 2021·Journal of Personalized Medicine·Guido VeitGergely L Lukacs
Aug 28, 2021·Journal of Personalized Medicine·Bente L AalbersHarry G M Heijerman

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