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. Author manuscript; available in PMC: 2019 Apr 8.
Published in final edited form as: Nat Med. 2018 Oct 8;24(11):1732–1742. doi: 10.1038/s41591-018-0200-x

Figure 5.

Figure 5

Corrector combinations rescue the ΔF508-CFTR function in human bronchial and nasal as well as mouse nasal epithelia. (a) Effect of indicated single correctors or corrector combinations on the Isc of primary human bronchial epithelia with CFTRΔF508/ΔF508 genotype (CF-HBE). (b) Quantification of the Fsk- and gen-stimulated current (ΔIsc Fsk + Gen, upper panel) in CF-HBE of five individuals homozygous for ΔF508 after single or combination of corrector treatment, expressed as percentage of WT-CFTR currents in WT-HBE from five donors. The fraction of potentiator independent Fsk-stimulated current is depicted in the lower panel. *P < 0.05, **P < 0.01 by paired two-tailed Student’s t-test in comparison to VX-809 (the precise P-values are listed in Supplementary Table 4). (c,d) Effect of VX-809 or 3C on the Isc of human CF nasal epithelia (CF-HNE) isolated from seventeen individuals with CFTRΔF508/ΔF508 genotype. Quantification of the CFTRinh-172 inhibited current is depicted in d. 3C (Fsk) shows 3C corrected Isc stimulated with forskolin alone (cells from 12 individuals) and cVX-770, indicating chronic (37˚C, 24 hours, 1 μM, cells from 5 individuals) treatment with VX-770. *P < 0.05, **P < 0.01 by unpaired two-tailed Student’s t-test. (e) Correlation between the functional correction in CF-HBE (n = cells from 5 individuals) and CF-HNE (n = cells from 17 individuals). The Pearson correlation coefficient and the associated P-value are shown. (f,g) Nasal potential difference (Vt) measurements in ΔF508 Cftrtm1EUR mice. Representative Vt recordings before (f, left panel) and after treatments with 3C (f, right panel). After perfusion of nasal epithelium with Cl--containing solution (Cl-) Vt changes were monitored after sequential addition of 100 μM amiloride (Amil), low Cl- + Fsk (10 μM) and 5 μM CFTRinh-172. Summary of the ΔVt results for Low Cl- + Fsk and CFTRinh-172 for 8 mice in 3 independent experiments are shown in g. The mean values are indicated. (h) NPD results in ΔF508 Cftrtm1EUR mice (n = 8 animals) in comparison to WT-CFTR mice (n = 42 animals for basline and Δamiloride; n = 17 animals for Δlow Cl- + Fsk and Δ CFTRinh-172)46. ns, not significant, *P <0.05 by two-sided Wilcoxon signed-rank test (g-h). Data in b, d-e and h are means ± SEM. The precise P-values are listed in Supplementary Table 4.