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
X
ABCC7 p.Gly551Asp 23757197:3:43
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:7:260
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:75:47
status: NEW
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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
X
ABCC7 p.Arg347Pro 23757197:78:26
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:80:60
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:103:43
status: NEW
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ABCC7 p.Gly1349Asp
X
ABCC7 p.Gly1349Asp 23757197:103:59
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:108:193
status: NEW
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ABCC7 p.Gly1349Asp
X
ABCC7 p.Gly1349Asp 23757197:108:206
status: NEW
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ABCC7 p.Asp1152His
X
ABCC7 p.Asp1152His 23757197:108:246
status: NEW
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ABCC7 p.Gly970Arg
X
ABCC7 p.Gly970Arg 23757197:108:233
status: NEW
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ABCC7 p.Glu193Lys
X
ABCC7 p.Glu193Lys 23757197:108:220
status: NEW
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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
X
ABCC7 p.Gly550Glu 23757197:122:26
status: NEW
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Some mutations, such as p.Gly550Glu, improve NBD1 stability [58]. Login to comment
123 ABCC7 p.Arg1070Trp
X
ABCC7 p.Arg1070Trp 23757197:123:27
status: NEW
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Other mutations, such as p.Arg1070Trp, improve the interaction between NBD1 and CL4 [60]. Login to comment
133 ABCC7 p.Gly551Asp
X
ABCC7 p.Gly551Asp 23757197:133:177
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:134:118
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:135:82
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:145:16
status: NEW
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Correction of p.Gly551Asp-CFTR gating defect was also demonstrated by measuring chloride concentration in the sweat. Login to comment
159 ABCC7 p.Gly551Asp
X
ABCC7 p.Gly551Asp 23757197:159:256
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:161:10
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:164:13
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:199:110
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:249:91
status: NEW
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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
X
ABCC7 p.Gly551Asp 23757197:250:83
status: NEW
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Interestingly, a recent clinical study has shown that KalydecoTM is effective on p.Gly551Asp patients aged 6-11 years [83]. Login to comment