ABCMdb

PMID: 23457166

Derichs N
Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis.
Eur Respir Rev. 2013 Mar 1;22(127):58-65. doi: 10.1183/09059180.00008412., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCC7 p.Gly551Asp Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. Login to comment 8 ABCC7 p.Gly551Asp KEYWORDS: CFTR modulators, cystic fibrosis, G551D mutation, ivacaftor, personalised medicine, VX-770 D orothy Hansine Andersen was the first person to comprehensively describe and document cystic fibrosis (CF) in the 1930s [1]. Login to comment 24 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* In fact, notwithstanding the common F508del variant, only four CFTR mutations have a frequency .0.1%: G551D, W1282X, G542X and N1303K, having a worldwide prevalence of around 1-3% each [9, 11]. Login to comment 28 ABCC7 p.Gly542* For example, G542X is a nonsense or stop mutation, where introduction of a premature termination codon (or stop codon) results in premature cessation of translation and production of truncated CFTR protein. Login to comment 31 ABCC7 p.Gly551Asp Class III mutations result in limited channel gating that arises from ineffectual binding of nucleotide; an example is G551D which accounts for 2-3% of CFTR mutations worldwide. Login to comment 76 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ASL hydration is achieved through establishment of an osmotic gradient by a predominant efflux of chloride ions through CFTR channels, coupled with a moderate influx of sodium ions through epithelial 100 80 60 40 20 0 Sweat chloride mmol&#b7;L -1 Sweat chloride in CF CFTR protein function % 20 0 40 60 80 100 >60 mmol&#b7;L-1 diagnostic cut-off for CF Normal Normal Carriers Carriers CF with pancreatic insufficiency Class I-III (F508del, G551D, W1282X) CF with pancreatic sufficiency Class IV-V (3849+10kbC-T, A455E) CBAVD with two CF mutations (R117H, 5T) CFTR-related disorder (pancreatitis, bronchiectasis, CBAVD) Adults ? Login to comment 144 ABCC7 p.Gly551Asp Ivacaftor, formerly known as VX-770, is a CFTR potentiator that specifically targets the Class III mutation, G551D. Login to comment 145 ABCC7 p.Gly551Asp The compound was initially identified using high-throughput screening from a library of 228,000 agents and subsequently validated using single channel patch-clamp measurements in Fischer Rat Thyroid cells expressing G551D-CFTR [52]. Login to comment 146 ABCC7 p.Gly551Asp The authors reported that 10 mM ivacaftor increased the open probability of G551D-CFTR channels by <6-fold (p,0.05). Login to comment 147 ABCC7 p.Gly551Asp These findings were validated in primary cultures of human bronchial epithelial (HBE) cells isolated from the bronchi of G551D-CF patients. Login to comment 149 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp In HBE cells with the G551D/F508del and F508del/F508del genotypes, ivacaftor was shown to potentiate CFTR-mediated chloride secretion, with the greatest effect seen in G551D/F508del cells (50% of wild-type CFTR activity) (fig. 3a). Login to comment 153 ABCC7 p.Gly551Asp Taken together, these preclinical results suggest that ivacaftor specifically targets and repairs the underlying gating defect caused by the G551D mutation. Login to comment 154 ABCC7 p.Gly551Asp Based on this evidence clinical trials were commenced in CF patients carrying at least one copy of the G551D-CFTR mutation, the results of which are discussed in the article by SERMET-GAUDELUS [55] in this issue of the European Respiratory Review. Login to comment 176 ABCC7 p.Gly551Asp One such modulator, the CFTR potentiator ivacaftor, is a first-in-class agent to be approved as an oral therapy for CF patients with the G551D-CFTR mutation and is a pertinent example of personalised medicine. Login to comment 180 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp 100 a) c) 50 15 10 5 0 CFTR activity % of wild-type control CBF Hz ASL volume % Untreated Treated with ivacaftor F508del/F508del G551D/F508del Ivacaftor M 20 b) 15 10 5 0 G551D/F508del-HBE Non-CF-HBE DMSO 30 nM VIP 10 &#b5;M IVA VIP+ IVA DMSO * # # 200 d) 175 150 125 100 75 DMSO 30 nM VIP 10-4 10-5 10-6 10-7 10-8 * Control Ivacaftor FIGURE 3. Login to comment 181 ABCC7 p.Gly551Asp Ivacaftor restores G551D-cystic fibrosis transmembrane conductance regulator (CFTR) function in human bronchial epithelial (HBE) primary cell cultures. Login to comment 183 ABCC7 p.Gly551Asp Ivacaftor increased the activity of G551D/F508del-CFTR to ,50% of wild-type (personal communication; F. van Goor, Vertex Pharmaceuticals Inc., Cambridge, MA, USA). Login to comment 188 ABCC7 p.Gly551Asp *: p,0.05, significant difference between DMSO and G551D/F508del-HBE; # : p,0.05, significant difference between DMSO and IVA alone. Login to comment 189 ABCC7 p.Gly551Asp c) Representative confocal microscopy image of G551D/F508del-HBE cultures treated with vehicle control or ivacaftor. Login to comment 192 ABCC7 p.Gly551Asp d) Dose-response curve of the change in ASL volume in G551D/F508del-HBE after application of ivacaftor at the indicated concentrations (n53-9). Login to comment