ABCMdb

PMID: 25732475

Yousef S, Solomon GM, Brody A, Rowe SM, Colin AA
Improved clinical and radiographic outcomes after treatment with ivacaftor in a young adult with cystic fibrosis with the P67L CFTR mutation.
Chest. 2015 Mar;147(3):e79-82. doi: 10.1378/chest.14-1198., [PubMed]

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No. Mutations Sentence Comment

0 ABCC7 p.Pro67Leu e journal.publications.chestnet.org Improved Clinical and Radiographic Outcomes After Treatment With Ivacaftor in a Young Adult With Cystic Fibrosis With the P67L CFTR Mutation Shatha Yousef, MD; George M. Solomon, MD; Alan Brody, MD; Steven M. Rowe, MD, MSPH; and Andrew A. Colin, MD The underlying cause of cystic fibrosis (CF) is the loss of epithelial chloride and bicarbonate transport due to mutations in the CF transmembrane conductance regulator (CFTR) gene encoding the CFTR protein. Login to comment 2 ABCC7 p.Arg117His Originally approved for the G511D CFTR mutation, ivacaftor is now approved for eight additional alleles exhibiting gating defects and has also been tested in R117H, a CFTR mutation with residual function that exhibits abnormal gating. Login to comment 3 ABCC7 p.Pro67Leu P67L is a class 4 conductance (nongating) mutation exhibiting residual CFTR function. Login to comment 4 ABCC7 p.Pro67Leu We report marked clinical improvement, normalization of spirometry, and dramatic reduction in radiographic structural airway changes after .1 year of treatment with ivacaftor in a young adult with the compound heterozygous genotype P67L/F508del CFTR. Login to comment 11 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp DOI: 10.1378/chest.14-1198 Despite major advances in management, cystic fibrosis (CF) remains an illness with high morbidity and mortality.1,2 The underlying cause of CF is the loss of epithelial chloride and bicarbonate transport due to mutations in the CF transmembrane conductance regulator (CFTR) gene encoding the CFTR protein.3 A new therapeutic approach involves improving the function of mutant CFTR.4 Ivacaftor (formerly VX-770) is a gene-specific CFTR potentiator that augments in vivo chloride transport in CFTR mutations affecting channel gating, such as G551D.5 Although marked improvements in spirometry, clinical outcome, and sweat chloride were observed in patients with G551D-CF treated with ivacaftor,4,6 its effect on structural lung disease has not been studied. Login to comment 12 ABCC7 p.Gly551Asp Moreover, although ivacaftor alone has minimal effect on F508del homozygous individuals,7 it has demonstrated in vitro efficacy for conductance mutations other than G551D by augmenting gating to supernormal levels8 but has not yet been Downloaded From: http://journal.publications.chestnet.org/ by a Semmelweis Egyetem User on 12/05/2015 studied clinically. Login to comment 13 ABCC7 p.Pro67Leu ABCC7 p.Pro67Leu This includes P67L, a class 4 conductance mutation that exhibits residual CFTR function and relatively preserved CFTR expression, has a worldwide prevalence of 0.2%, and is the sixth most common mutation in Scotland.9 We report a case of a patient with CF who is a complex heterozygote for P67L/F508del with severe CF lung disease who improved significantly shortly after starting treatment with ivacaftor, including evidence of resolving structural lung disease. Login to comment 14 ABCC7 p.Pro67Leu Case Report The patient is an 18-year-old woman of Scottish descent with genotype F508del/P67L. Login to comment 34 ABCC7 p.Pro67Leu ABCC7 p.Pro67Leu P67L is generally considered a CFTR mutation with reduced conductance.12 Furthermore, Sosnay and colleagues13 reported lower levels of mature glycosylated protein compared with wild-type CFTR (low band C/B ratio), suggesting an additional abnormality caused by ineffective maturation of P67L. Login to comment 35 ABCC7 p.Pro67Leu Van Goor et al12 studied the in vitro effect of ivacaftor on multiple mutant CFTR forms due to missense mutations, including mutations that cause abnormal protein processing and reduced CFTR activity at the plasma membrane, such as P67L. Login to comment 36 ABCC7 p.Pro67Leu In vitro, ivacaftor caused a significant increase in chloride current in epithelial cells expressing these mutations.12 Combined with data illustrated by this case, results strongly indicate that P67L is among the mutations that can Figure 1 - Comparison of the average FEV1 of all available measurements obtained during the years prior to ivacaftor and after the start of ivacaftor treatment. Login to comment 39 ABCC7 p.Pro67Leu Moreover, the observed course of this patient supports the notion that ivacaftor could exhibit a class effect on CFTR mutations with decreased conductance but residual function and expression, such as P67L. Login to comment 41 ABCC7 p.Gly551Asp Improvements in structural lung disease detected by serial high-resolution CT scan and the change in sputum microbiology suggest that ivacaftor could potentially alter the natural history of the disease, as also recently observed among G551D patients in a post-approval study.14 These clinical measures may be suitable outcome measures for patients in future clinical trials evaluating the efficacy of CFTR modulators. Login to comment 44 ABCC7 p.Arg117His ABCC7 p.Pro67Leu Currently, evaluation of conductance mutations has been limited to the R117H mutation, which also exhibits abnormal gating.15 Although ivacaftor has been reported to reduce the stability of some CFTR forms in vitro, including P67L, any detrimental effect on cell surface levels was not apparent based on a robust and sustained clinical response in this individual.16,17 Our positive experience emphasizes the need for definitive studies to test the potential benefit of ivacaftor for patients with CF with nongating missense mutations. Login to comment