title: Therapeutic benefit observed with the CFTR potentiator, ivacaftor, in a CF patient homozygous for the W1282X CFTR nonsense mutation.
abstract: Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) gene result in nonfunctional CFTR protein and are the proximate cause of ~11% of CF causing alleles. Aminoglycosides and other novel agents are known to induce translational readthrough of PTCs, a potential therapeutic approach. Among PTCs, W1282X CFTR is unique, as it is a C-terminal CFTR mutation that can exhibit partial activity, even in the truncated state. The potentiator ivacaftor (VX-770) is approved for treating CF patients with G551D and other gating mutations. Based on previous studies demonstrating the beneficial effect of ivacaftor for PTC mutations following readthrough in vitro, we hypothesized that ivacaftor may enhance CFTR activity in CF patients expressing W1282X CFTR, and could be further enhanced by readthrough. Ivacaftor significantly increased CFTR activity in W1282X-expressing cells compared to R1162X CFTR cells, and was further enhanced by readthrough with the aminoglycoside G418. Primary nasal epithelial cells from a W1282X homozygous patient showed improved CFTR function in the presence of ivacaftor. Upon ivacaftor administration to the same patient, there was significant improvement in pulmonary exacerbation frequency, BMI, and insulin requirement, whereas FEV1remained stable over 3years. These studies suggest that ivacaftor may have moderate clinical benefit in patients with preserved expression of the W1282X CFTR mutation by stimulating residual activity of the truncated protein, suggesting the need for further studies including the addition of efficacious readthrough agents.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Venkateshwar
authors.initials: V
authors.lastname: Mutyam
authors.affiliation: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Emily Falk
authors.initials: EF
authors.lastname: Libby
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Peng
authors.affiliation: Department of Medicine, University of Pennsylvania Medical Center, PA, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Hadjiliadis
authors.affiliation: Department of Medicine, University of Pennsylvania Medical Center, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonk
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Solomon
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: smrowe@uab.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
mesh_terms: D006801:Humans; D000627:Aminophenols / Q000494:pharmacology; D065101:Chloride Channel Agonists / Q000494:pharmacology; D018389:Codon, Nonsense; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D006720:Homozygote; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D015363:Quinolones / Q000494:pharmacology; D016896:Treatment Outcome; D005260:Female; D000328:Adult
chemical_list: D000627:Aminophenols; C505032:CFTR protein, human; D065101:Chloride Channel Agonists; D018389:Codon, Nonsense; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; D015363:Quinolones
keywords: CFTR potentiator; Ivacaftor; PTC mutations; Readthrough; W1282X