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Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators
Sangwoo T. Han, … , Eric J. Sorscher, Garry R. Cutting
Sangwoo T. Han, … , Eric J. Sorscher, Garry R. Cutting
Published July 25, 2018
Citation Information: JCI Insight. 2018;3(14):e121159. https://doi.org/10.1172/jci.insight.121159.
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Research Article Genetics Therapeutics

Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators

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Abstract

Treatment of individuals with cystic fibrosis (CF) has been transformed by small molecule therapies that target select pathogenic variants in the CF transmembrane conductance regulator (CFTR). To expand treatment eligibility, we stably expressed 43 rare missense CFTR variants associated with moderate CF from a single site in the genome of human CF bronchial epithelial (CFBE41o–) cells. The magnitude of drug response was highly correlated with residual CFTR function for the potentiator ivacaftor, the corrector lumacaftor, and ivacaftor-lumacaftor combination therapy. Response of a second set of 16 variants expressed stably in Fischer rat thyroid (FRT) cells showed nearly identical correlations. Subsets of variants were identified that demonstrated statistically significantly higher responses to specific treatments. Furthermore, nearly all variants studied in CFBE cells (40 of 43) and FRT cells (13 of 16) demonstrated greater response to ivacaftor-lumacaftor combination therapy than either modulator alone. Together, these variants represent 87% of individuals in the CFTR2 database with at least 1 missense variant. Thus, our results indicate that most individuals with CF carrying missense variants are (a) likely to respond modestly to currently available modulator therapy, while a small fraction will have pronounced responses, and (b) likely to derive the greatest benefit from combination therapy.

Authors

Sangwoo T. Han, Andras Rab, Matthew J. Pellicore, Emily F. Davis, Allison F. McCague, Taylor A. Evans, Anya T. Joynt, Zhongzhou Lu, Zhiwei Cai, Karen S. Raraigh, Jeong S. Hong, David N. Sheppard, Eric J. Sorscher, Garry R. Cutting

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Figure 1

Ivacaftor response correlates with residual function.

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Ivacaftor response correlates with residual function.
(A) Ivacaftor (10 ...
(A) Ivacaftor (10 μM) enhanced CFTR function compared with residual forskolin-stimulated (10 μM) CFTR function for 45 variants expressed in CF bronchial epithelial (CFBE) cells. Each variant measured n ≥ 3 and was plotted as mean ± SEM on both axes. (B) Ivacaftor (5 μM) enhanced CFTR function compared with residual forskolin-stimulated (5 μM) CFTR function for 18 variants expressed in Fisher rat thyroid (FRT) cells. Each variant measured n ≥ 3 and was plotted as mean ± SEM on both axes. (C) Separation of variants based on their fold response to ivacaftor. Response of cell lines expressing G551D (CFBE), G551D (FRT), S1159F, and S1159P were designated as outliers by demonstrating fold response greater than 2 SD beyond the mean fold response of all variants studied in CFBE and FRT cells and labeled as high-response variants. Intermediate-response variants were those that remained outliers when high-response variants were removed from the comparison. All remaining variants were classified as modest response. Lines through data points represent the mean value ± 1 SD for modest-response variants and mean of intermediate- and high-response variants. (D) Previously published data collected from FRT* cells (18, 19) of nongating variants plotted as in A and B. (E) Comparison of trend lines of modest-response variants identified in CFBE and FRT studies compared with nongating variants identified in FRT* cells. Correlation (r) values calculated using Pearson linear correlation.

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