ABCMdb

PMID: 23457168

Elborn JS
The impact of personalised therapies on respiratory medicine.
Eur Respir Rev. 2013 Mar 1;22(127):72-4. doi: 10.1183/09059180.00008212., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCC7 p.Gly551Asp Pivotal studies in patients with a G551D mutation, the most common Class III mutation, have demonstrated significant improvements in clinically important outcomes such as spirometry and exacerbations. Login to comment 7 ABCC7 p.Gly551Asp Sweat chloride was significantly reduced demonstrating a functional effect on the dysfunctional CFTR protein produced by the G551D mutation. Login to comment 29 ABCC7 p.Gly551Asp The recent identification of the ability of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, to treat some patients with cystic fibrosis (CF) is the first example in which a stratified medicine approach has resulted in a major change in therapy for patients with this disease who carry the gating channel mutation, G551D [15]. Login to comment 31 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp The candidate agent was subsequently shown to increase the channel opening probability of G551D CFTR by approximately six-fold and to partially restore fluid regulation and cilia beating in cultured CF human bronchial epithelia with the G551D/F508del genotype [3, 16]. Login to comment 33 ABCC7 p.Gly551Asp The efficacy and safety of ivacaftor was evaluated in two 48-week, randomised, double-blind, placebo-controlled trials in patients aged 6-11 yrs (ENVISION study) and patients aged o12 yrs (STRIVE study) who have at least one copy of the G551D-CFTR mutation [4]. Login to comment 40 ABCC7 p.Gly551Asp The reason for this is clear; ivacaftor is a CFTR potentiator that targets gating defects in G551D-CFTR channels. Login to comment 42 ABCC7 p.Gly551Asp Emerging CFTR modulators Ivacaftor, the first CFTR modulator to be approved for clinical use, can be only prescribed to approximately 4-5% of CF patients who have the G551D mutation. Login to comment 52 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly542* This optimism must TABLE 1 Mechanism of action and targets of emerging cystic fibrosis transmembrane conductance regulator (CFTR) modulators Mutation class Nature of defect Example mutations Pancreatic function# Modulator strategy Agents in development I Biosynthesis G542X Insufficient Suppressor Suppressor and potentiator" Ataluren II Trafficking F508del Insufficient Corrector Corrector plus potentiator VX-809 plus ivacaftor+ VX-661 plus ivacaftor+ III Channel gating G551D Insufficient Potentiator Ivacaftor (FDA approved, G551D) Other gating mutations?" Login to comment 53 ABCC7 p.Arg117His IV Channel conductance R117H Sufficient Potentiator?" Login to comment