ABCMdb

PMID: 20829696

Sloane PA, Rowe SM
Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis.
Curr Opin Pulm Med. 2010 Nov;16(6):591-7., [PubMed]

Sentences

No. Mutations Sentence Comment

24 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Class III and IV CFTR mutations are characterized by full-length CFTR that reaches the cell surface but exhibit reduced ion transport activity owing to abnormal channel gating (Class III, e.g. G551D) or reduced conductivity of the ion channel pore (Class IV, e.g. R117H). Login to comment 32 ABCC7 p.Gly551Asp CFTR potentiators are currently in human clinical trials (VX-770, green chevron) for patients with G551D and F508del CFTR. Login to comment 40 ABCC7 p.Gly551Asp G551D CFTR represents an archetype CFTR allele for this category of agents, as it exhibits normal surface expression and half-life, but confers a severe defect in channel gating owing to an amino acid substitution in the adenosine triphosphate (ATP) binding pocket within the nucleotide binding domains [14]. Login to comment 48 ABCC7 p.Gly551Asp Secondary testing of a lead compound developed by Vertex Pharmaceuticals (Cambridge, Massachusetts, USA), VX-770, indicated robust activation of mutant CFTR, including G551D expressed in heterologous cell culture systems and primary airway epithelial cell monolayers. Login to comment 51 ABCC7 p.Gly551Asp Although the binding site of this molecule has not been reported, other agents (e.g. VRT-532) that exhibit potentiator activity have been shown to directly bind F508del CFTR as indicated by protease stability experiments [22], and have also been shown to increase the ATPase activity (in addition to chloride conductance) of G551D CFTR [23 ]. Login to comment 52 ABCC7 p.Gly551Asp Testing of VX-770 has been conducted in CF individuals harboring at least one G551D CFTR mutation. Login to comment 58 ABCC7 p.Gly551Asp VX-770 has now progressed to phase 3 testing in CF individuals harboring G551D (Clinical Trials.gov reference numbers NCT00909532 and NTC00909727) and phase 2 testing in individuals homozygous for F508del (Clinical Trials.- gov reference number NCT00953706). Login to comment 92 ABCC7 p.Tyr122* A trial examining systemic gentamicin in seven French individuals with Y122X CFTR, a mutation highly susceptible to readthrough, also indicated rescue of CFTR activity in the airway and sweat duct [53]. Login to comment 100 ABCC7 p.Gly542* Surface localized full-length CFTR was substantially improved in cross-sections of intestinal tissues following administration to CF mice carrying the G542X mutation and restored CFTR function by Ussing chamber analysis in intestinal samples of mice after 2 weeks of treatment with ataluren. Login to comment 104 ABCC7 p.Trp1282* The reasons for failure are not completely clear, but include the challenge of NPD studies in multicenter trials (a critique that has been subsequently addressed by improvement in the testing method [72]), relative susceptibility of the W1282X mutation found commonly in Israel [73], and genetic founder effects, including the degree of CFTR mRNA expression at baseline [70 ,74]. Login to comment