Therapeutic benefit observed with the CFTR potentiator, ivacaftor, in a CF patient homozygous for the W1282X CFTR nonsense mutation Venkateshwar Mutyam,

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Therapeutic benefit observed with the CFTR potentiator, ivacaftor, in a CF patient homozygous for the W1282X CFTR nonsense mutation Venkateshwar Mutyam, Emily Falk Libby, Ning Peng, Denis Hadjiliadis, Michael Bonk, George M. Solomon, Steven M. Rowe Journal of Cystic Fibrosis Volume 16, Issue 1, Pages 24-29 (January 2017) DOI: 10.1016/j.jcf.2016.09.005 Copyright © 2016 European Cystic Fibrosis Society Terms and Conditions

Fig. 1 Effect of ivacaftor in vitro, in CFBE and FRT W1282X cells and W1282X homozygous primary nasal epithelial cells derived from the case subject. (A) Short circuit (Isc) tracings of CFBE41o- cells transduced with W1282X or R1162X cDNA, pretreated with DMSO control or G418 (250μg/mL) for 48h. FSK=forskolin. (B) Summary graph of A. (C) Raw Gt tracings of FRT cell monolayers transduced with R1162X and W1282X CFTR. (D) Summary graph of C showing response to forskolin and VX-770. G418 treatment significantly enhanced forskolin-mediated Isc in both R1162X and W1282X compared to vehicle and the synergistic effect of ivacaftor with G418 was significant in W1282X compared to R1162X cells. (E) Representative tracings of the short circuit current (Isc) in HNE W1282X/W1282X cells (n=3/each condition) incubated with either ivacaftor (10μM) or DMSO vehicle for 48h, where forskolin (20μM; FSK) and ivacaftor (10μM VX-770) were administered acutely to stimulate CFTR activity followed by the addition of CFTR-specific inhibitor, CFTRInh-172 (10μM). (F) Forskolin-induced CFTR activity was enhanced significantly in HNE cells incubated with ivacaftor compared to DMSO-treated cells. (G) CFTR mRNA levels detected by real-time reverse transcriptase PCR, HNE W1282X/W1282X expressed 0.4-fold as compared to HNE donors expressing wild type CFTR and cultured with the same method. A second HNE donor heterozygous for nonsense mutations is shown for comparison. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. Journal of Cystic Fibrosis 2017 16, 24-29DOI: (10.1016/j.jcf.2016.09.005) Copyright © 2016 European Cystic Fibrosis Society Terms and Conditions

Fig. 2 Effect of ivacaftor on lung function, BMI, and exacerbation frequencies: (A) Pre- and post-ivacaftor measurements of FEV1% predicted from 2007 to 2016. Lines represent the regression analysis line for each treatment period. Following initiation of ivacaftor, there was no significant change in mean FEV1% predicted or the rate of FEV1% predicted decline. (B) BMI obtained during the study period. Rate of change in BMI improved significantly with ivacaftor administration (P<0.001). (C) The number of months with and without an exacerbation, for the treatment period before and after initiation of ivacaftor. Statistical comparison by chi square. (D) Total daily insulin intake requirements before and after initiation of ivacaftor. Statistical comparisons by paired t-test. *P<0.05, ****P<0.0001. Journal of Cystic Fibrosis 2017 16, 24-29DOI: (10.1016/j.jcf.2016.09.005) Copyright © 2016 European Cystic Fibrosis Society Terms and Conditions