ABCMdb

PMID: 23757197

Galietta LJ
Managing the underlying cause of cystic fibrosis: a future role for potentiators and correctors.
Paediatr Drugs. 2013 Oct;15(5):393-402. doi: 10.1007/s40272-013-0035-3., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCC7 p.Gly551Asp In particular, class 3 mutations such as p.Gly551Asp strongly decrease the time spent by CFTR in the open state (gating defect). Login to comment 7 ABCC7 p.Gly551Asp The potentiator KalydecoTM (also known as Ivacaftor or VX-770), developed by Vertex Pharmaceuticals, has been recently approved by the US FDA and the European Medicines Agency (EMA) for the treatment of CF patients carrying at least one CFTR allele with the p.Gly551Asp mutation (2-5 % of all patients). Login to comment 75 ABCC7 p.Gly551Asp Class 3 includes missense mutations, such as P.Gly551Asp (glycine 551 mutated to aspartic acid), that strongly impair channel gating. Login to comment 78 ABCC7 p.Arg347Pro Class 4 mutations (e.g. p.Arg347Pro), Fig. 2 Molecular defects associated with cystic fibrosis (CF) mutations and possibilities for pharmacological correction. Login to comment 80 ABCC7 p.Gly551Asp Missense mutations belonging to class 3 mutations such as p.Gly551Asp strongly decrease the time spent by the channel in the open state. Login to comment 103 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp In particular, class 3 mutations such as p.Gly551Asp and p.Gly1349Asp, which cause a gating defect even more severe than that of p.Phe508del but no trafficking problems, are highly responsive to genistein and other potentiators [19, 39, 40]. Login to comment 108 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp ABCC7 p.Asp1152His ABCC7 p.Gly970Arg ABCC7 p.Glu193Lys There are several studies describing the discovery of very effective potentiators, in many cases with nanomolar potency, that can rescue channel activity not only of p.Phe508del, but also of p.Gly551Asp, p.Gly1349Asp, p.Glu193Lys, p.Gly970Arg, p.Asp1152His, and other mutations [51, 52]. Login to comment 122 ABCC7 p.Gly550Glu Some mutations, such as p.Gly550Glu, improve NBD1 stability [58]. Login to comment 123 ABCC7 p.Arg1070Trp Other mutations, such as p.Arg1070Trp, improve the interaction between NBD1 and CL4 [60]. Login to comment 133 ABCC7 p.Gly551Asp Optimization by medicinal chemistry of one of the active chemical classes generated VX-770, a molecule with very high (nanomolar) potency and efficacy on p.Phe508del-CFTR and p.Gly551Asp [47]. Login to comment 134 ABCC7 p.Gly551Asp VX-770, named Ivacaftor, was tested in phase II and III clinical trials on patients having at least one copy of the p.Gly551Asp mutation. Login to comment 135 ABCC7 p.Gly551Asp The reason for testing the experimental drug only on such patients was that the p.Gly551Asp mutation causes a 'pure` gating defect that is highly responsive to this potentiator. Login to comment 145 ABCC7 p.Gly551Asp Correction of p.Gly551Asp-CFTR gating defect was also demonstrated by measuring chloride concentration in the sweat. Login to comment 159 ABCC7 p.Gly551Asp The very positive outcome of treatment with Ivacaftor in clinical trials determined its approval by the US FDA, and subsequently by the European Medicines Agency (EMA), for the treatment of CF patients aged C6 years and carrying at least one copy of the p.Gly551Asp mutation. Login to comment 161 ABCC7 p.Gly551Asp Indeed, p.Gly551Asp has a frequency not exceeding 3-5 % in Northern Europe or Northern America and less than 1 % in other countries, such as Italy. Login to comment 164 ABCC7 p.Gly551Asp The sum of p.Gly551Asp and other class 3 mutations probably accounts for 5-10 % of all CF patients. Login to comment 199 ABCC7 p.Gly551Asp This is a modest improvement in CFTR function if compared with the 48-mM decrease generated by Ivacaftor in p.Gly551Asp patients. Login to comment 249 ABCC7 p.Gly551Asp However, approval of the use of KalydecoTM for CF patients with mutations different from p.Gly551Asp requires specific clinical studies. Login to comment 250 ABCC7 p.Gly551Asp Interestingly, a recent clinical study has shown that KalydecoTM is effective on p.Gly551Asp patients aged 6-11 years [83]. Login to comment