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
References
Aug 27, 1992·Nature·G M DenningM J Welsh
Nov 7, 2000·Annals of Tropical Paediatrics·A Abdul WahabG al Thani
May 15, 2002·Human Mutation·Joseph L BobadillaPhilip M Farrell
Aug 6, 2002·The Journal of Biological Chemistry·Tonghui MaA S Verkman
Mar 13, 2003·Journal of Tropical Pediatrics·A Abdul Wahab
Jan 8, 2010·American Journal of Physiology. Cell Physiology·Nicoletta PedemonteLuis J V Galietta
Aug 27, 2013·Nature Genetics·Patrick R SosnayGarry R Cutting
Feb 22, 2014·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Steven V MolinskiChristine E Bear
Nov 19, 2014·Nature Reviews. Genetics·Garry R Cutting
Mar 5, 2015·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Anabela S RamalhoMargarida D Amaral
May 4, 2016·Lancet·J Stuart Elborn
Nov 30, 2016·The Journal of Biological Chemistry·Peter M HaggieAlan S Verkman
Jul 2, 2017·EMBO Molecular Medicine·Steven V MolinskiChristine E Bear
Oct 27, 2017·Current Opinion in Pharmacology·Kang-Yang JihTzyh-Chang Hwang
Mar 15, 2018·Current Opinion in Pediatrics·Elizabeth B Burgener, Richard B Moss
Jun 16, 2018·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Puay-Wah PhuanAlan S Verkman
Oct 20, 2018·The New England Journal of Medicine·Dominic KeatingUNKNOWN VX16-445-001 Study Group
Jun 1, 2015·International Journal of Pediatrics & Adolescent Medicine·Hanaa Banjar, Gerhild Angyalosi
Jun 6, 2019·The Journal of General Physiology·Han-I YehTzyh-Chang Hwang
Jun 22, 2019·Science·Fangyu LiuJue Chen
Oct 30, 2019·Seminars in Respiratory and Critical Care Medicine·Senne Cuyx, Kris De Boeck
Nov 5, 2019·Lancet·Harry G M HeijermanUNKNOWN VX17-445-103 Trial Group
Nov 8, 2019·The New England Journal of Medicine·Peter G MiddletonUNKNOWN VX17-445-102 Study Group
Nov 13, 2019·Pediatric Pulmonology·Disha JoshiEric J Sorscher
Nov 30, 2019·Scientific Reports·Puay-Wah PhuanAlan S Verkman
Citations
Nov 11, 2020·Journal of Personalized Medicine·Onofrio LaselvaChristine E Bear
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