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 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 FEV1 remained stable over 3 years. 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.

Effect of one-year lumacaftor–ivacaftor treatment on glucose tolerance abnormalities in cystic fibrosis patients

“…The second study reported lower glycemic variability upon GCM at 6 months post-treatment in nine CF subjects with early AGT [7] . Other small studies reported a positive effect of ivacaftor on glucose metabolism in CF patients with G551D or Delta F508/S549R mutations [8][9][10][11][12][13] .…”

Positional effects of premature termination codons on the biochemical and biophysical properties of CFTR

“…Lumacaftor and Tezacaftor) to enhance the function of the truncated protein. However, it is unclear if these CFTR modulators, which are now clinical medicines, can be universally applied to PTCs since the relationship between the position of the PTC and the function of the truncated protein has yet to be established (Wang et al 2007;Haggie et al 2017;Mutyam et al 2017;Xue et al 2017;Yeh et al 2019b; ClinicalTrials.gov Identifier: NCT03624101 (https://clinicaltrials.gov/ct2/show/NCT03624101)). In theory, reagents that can promote read-through have the greatest potential for overcoming PTCs, and indeed compounds such as Ataluren and G418 have been shown to increase the expression of read-through CFTR in vitro (Howard et al 1996;Roy et al 2016) and in vivo (Wilschanski et al 2003;Du et al 2008).…”

“…VX-770) and correctors (e.g. VX-809 and VX-661), both now available in clinics, could enhance the function and the expression of the protein (Yeh et al 2015;Yeh et al 2019b;Wang et al 2016;Haggie et al 2017;Mutyam et al 2017; ClinicalTrials.gov Identifier: NCT03624101 (https://clinicaltrials.gov/ct2/show/NCT03624101)). Aside from these FDA-approved CFTR modulators, future development of a novel CFTR stabilizer (e.g.…”

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

“…Furthermore, incorporation of a foreign amino acid may result in full-length but misfolded and/or nonfunctional proteins. PTC suppression in combination with other modulators, such as lumacaftor and/or ivacaftor, has demonstrated to promote a further rescue of expression and function of CFTR PTC mutations (Xue et al, 2014;Mutyam et al, 2016;Mutyam et al, 2017;Xue et al, 2017;Pranke et al, 2018;. These approaches should be exploited in future clinical studies.…”