ABCMdb

PMID: 24925916

Mall MA, Hartl D
CFTR: cystic fibrosis and beyond.
Eur Respir J. 2014 Oct;44(4):1042-54. doi: 10.1183/09031936.00228013. Epub 2014 Jun 12., [PubMed]

Sentences

No. Mutations Sentence Comment

78 ABCC7 p.Gly551Asp Ivacaftor was approved in 2012 as the first mutation-specific therapy for CF patients carrying the G551D gating mutation [63, 64]. Login to comment 79 ABCC7 p.Gly551Asp The G551D mutation is expressed and inserted into the apical plasma membrane at normal levels; however, the ATP-induced dimerisation of the two NBDs required for normal gating of the CFTR channel is defective, resulting in a very low open probability [61]. Login to comment 80 ABCC7 p.Gly551Asp Although its mechanism of action remains incompletely understood, functional studies at the single channel level demonstrated that ivacaftor improved gating and increased the open probability of the G551D channel [61, 65]. Login to comment 81 ABCC7 p.Gly551Asp In cultured human CF bronchial epithelial cells, this effect rescued G551D-mediated Cl-transport to ,50% of wild-type CFTR function, and reduced increased ENaC-mediated Na+ and fluid absorption [61]. Login to comment 85 ABCC7 p.Gly551Asp Similar effects with an overall improvement of FEV1 % pred of 12.5% were observed in younger CF patients (6-11 years of age) with a G551D mutation, and it was shown that ivacaftor improves the lung clearance index in children with CF with normal spirometry [64, 66]. Login to comment 87 ABCC7 p.Gly551Asp The CFTR potentiator creates opportunities for personalised medicine for CF However, because the G551D mutation affects only ,4% of CF patients worldwide, considerable challenges remain that need to be overcome before a larger group of patients can benefit from these novel CFTR modulator therapies. Login to comment 88 ABCC7 p.Gly551Asp In this context, recent in vitro studies demonstrated that ivacaftor can improve the open probability and, thus, potentiate other non-G551D gating mutations, as well as other rare CFTR mutations that cause mild defects in processing and/or conductance [74, 75]. Login to comment 90 ABCC7 p.Gly551Asp ABCC7 p.Arg117His This hypothesis is currently being tested in a series of clinical trials in patients with non-G551D gating mutations and the pancreatic sufficient mutation R117H. Login to comment