ABCMdb

PMID: 22058188

Elborn JS
Fixing cystic fibrosis CFTR with correctors and potentiators. Off to a good start.
Thorax. 2012 Jan;67(1):4-5. Epub 2011 Nov 5., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp The most straightforward is to use molecules that potentiate dysfunctional CFTR which reaches the cell membrane in patients with specific mutations associated with abnormal gating.11 These mutations, classified as class III mutations, account for around 5% of mutant alleles in people with CF.12 The most frequently occurring of these gating mutations is G551D.12 13 In two recently published studies, a proof of concept14 and subsequent phase III study15 in patients with at least one G551D mutation, the potentiator VX-770 (Vertex Pharmaceuticals, Cambridge, Massachusetts, USA) was shown to have significant positive effects on nasal electrophysiology and sweat chloride concentrations. Login to comment 11 ABCC7 p.Gly551Asp In addition to a substantial reduction in pulmonary exacerbations, this strongly suggests that VX-770 in patients with G551D is a disease-modifying therapy. Login to comment 13 ABCC7 p.Gly551Asp In vitro studies using CF epithelial cell lines show that the gating mutations respond to VX-770 in a similar manner to the G551D mutation in vitro. Login to comment 14 ABCC7 p.Gly551Asp There are no clinical data on patients with these mutations but there is no reason to anticipate a different clinical response from patients with G551D. Login to comment 17 ABCC7 p.Arg117His The most common of these mutations is the R117H mutation, which when found in cis with a 5Tsplice variant (IVS8-T5) and a second severe CF mutation results in classic CF.13 Further studies are required in this larger patient group. Login to comment 19 ABCC7 p.Gly551Asp F508del is primarily a class II mutation and results from misfolding of mutant CFTR, which is mostly degraded intracellularly in the proteasome and so does not reach the cell membrane.16 However, in vitro observations using cooled cells and compounds which overcome the proteasomal disposal show that it is possible to make F508del bypass the proteasomal degradation system, resulting in it being expressed at the cell membrane.16e18 At the cell membrane F508del then behaves as a gating mutation similar to G551D and can be activated with correctors such as VX-770.15 A number of in vitro compounds have been shown to have this effect, so correcting the F508del mutation. Login to comment 24 ABCC7 p.Gly551Asp This compares to a much larger reduction in sweat chloride concentration of around 60 mmol/litre in patients with G551D treated with VX-770.15 No significant changes were seen in CFTR function using nasal potential difference or maturation of CFTR protein and no changes were demonstrated in lung function or Correspondence to Professor J Stuart Elborn, Professor of Respiratory Medicine, QUB and, Director of Centre for Infection and Immunity,Queen`s University, Health Sciences Building, 97 Lisburn Road, Belfast, BT9 7BL, UK; s.elborn@qub.ac.uk Thorax January 2012 Vol 67 No 1 Editorial group.bmj.comon October 25, 2012 - Published bythorax.bmj.comDownloaded from patient-reported outcomes. Login to comment 26 ABCC7 p.Gly551Asp Although the magnitude of the effect of VX-890 on sweat chloride concentrations in people with CF homozygous for the F508del CFTR mutation is considerably lower than the impact of the potentiator VX-770 in patients with G551D mutations, the data from this study are encouraging as they demonstrate that it is possible to have an electrophysiological effect following correction of F508del CFTR. Login to comment 34 ABCC7 p.Gly551Asp The studies with VX-770 in patients with G551D indicate that the CFTR mutant protein is tractable with a small molecule drug and this translates into important and almost certainly disease-modifying improvements in people with CF and a gating mutation. Login to comment 45 ABCC7 p.Gly551Asp The clinical trials of VX-770 and VX-809 demonstrate a wide international collaboration involving North America, Europe and Australasia working closely together to ensure these clinical trials are delivered as quickly as possible despite the relatively small number of patients, particularly with G551D mutations. Login to comment