ABCMdb

PMID: 23069118

Thursfield RM, Davies JC
Cystic Fibrosis: therapies targeting specific gene defects.
Paediatr Respir Rev. 2012 Dec;13(4):215-9. doi: 10.1016/j.prrv.2012.04.003. Epub 2012 May 9., [PubMed]

Sentences

No. Mutations Sentence Comment

31 ABCC7 p.Trp1282* Examples of class I mutations include Trp1282X (previously W1282X) and Gly542X. Login to comment 39 ABCC7 p.Trp1282* Trp1282X previously termed W1282X] II Trafficking mutations: Misfolded protein fails to traffic to the apical cell surface and instead is degraded by intracellular processes [eg. Login to comment 41 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Gly551Asp previously termed G551D] IV Decreased conductivity: Protein reaches the cell surface but the abnormal conformation of the pore leads to poor conductance of chloride ions [eg. Login to comment 42 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Gln1412* Arg117His previously termed R117H] V Splicing defect: leads to decreased amount of CFTR protein at the cell surface [eg 3849+10 kb C>T] VI Functional but unstable with decreased half life at the cell surface [eg Gln1412X previously termed Q1412X] R.M. Thursfield, J.C. Davies / Paediatric Respiratory Reviews (2012) 215-219216 difference (nPD) measurement. Login to comment 74 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Further trials at different doses are ongoing.31 The exciting clinical results of VX-770 in patients with the class III mutation, Gly551Asp (previously G551D), appear to have recatalysed the field; other small molecules for class II mutations are being developed by Vertex, Pfizer, Genzyme and GSK, an endeavour supported strongly by the US CFF.32 However, recent recognition that two different misfolding steps may need, independently, to be corrected, illustrates the huge task ahead. Login to comment 75 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Further trials at different doses are ongoing.31 The exciting clinical results of VX-770 in patients with the class III mutation, Gly551Asp (previously G551D), appear to have recatalysed the field; other small molecules for class II mutations are being developed by Vertex, Pfizer, Genzyme and GSK, an endeavour supported strongly by the US CFF.32 However, recent recognition that two different misfolding steps may need, independently, to be corrected, illustrates the huge task ahead. Login to comment 77 ABCC7 p.Gly551Asp Class III mutations are found in around 5% of the CF population with Gly551Asp being by far the most common. Login to comment 78 ABCC7 p.Gly551Asp Class III mutations are found in around 5% of the CF population with Gly551Asp being by far the most common. Login to comment 79 ABCC7 p.Gly551Asp Initial phase II studies in patients with the Gly551Asp mutation demonstrated sweat chloride reductions of almost 60 mmol and significant, dose-related changes in nasal PD.36 Randomised, double-blind, placebo-controlled, multinational phase 3 studies in adults and children over the age of 6 have confirmed this effect and demonstrated significant improvements in lung function of around 17% of baseline, which were maintained out to 48 weeks. Login to comment 80 ABCC7 p.Gly551Asp Initial phase II studies in patients with the Gly551Asp mutation demonstrated sweat chloride reductions of almost 60 mmol and significant, dose-related changes in nasal PD.36 Randomised, double-blind, placebo-controlled, multinational phase 3 studies in adults and children over the age of 6 have confirmed this effect and demonstrated significant improvements in lung function of around 17% of baseline, which were maintained out to 48 weeks. Login to comment 84 ABCC7 p.Gly551Asp Gly551Asp patients were studied to optimise homogeneity, but in vitro data support the action of this drug on other gating mutations, all of which are relatively rare.39 Additionally, as discussed above, small amounts of CFTR may reach the cell surface in class II mutations, and this could further increase with correctors raising the hypothesis that potentiating the activity of class II mutated CFTR (or classes IV, V and VI) could lead to clinical benefits. Login to comment 85 ABCC7 p.Gly551Asp Gly551Asp patients were studied to optimise homogeneity, but in vitro data support the action of this drug on other gating mutations, all of which are relatively rare.39 Additionally, as discussed above, small amounts of CFTR may reach the cell surface in class II mutations, and this could further increase with correctors raising the hypothesis that potentiating the activity of class II mutated CFTR (or classes IV, V and VI) could lead to clinical benefits. Login to comment