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Author Notes:

Address correspondence to: Garry Cutting, The Johns Hopkins Medical Institutions, 733 North Broadway, BRB 559, Baltimore, Maryland 21205, USA. Phone: 410.614.0211; Email: gcutting@jhmi.edu

STH designed studies for CFBE cells, generated and analyzed data for CFBE cells, and wrote the manuscript.

AR designed studies for FRT cells, generated and analyzed data for FRT cells, and reviewed the manuscript.

MJP, EFD, AFM, TAE, ATJ, and ZL contributed to collection of data for CFBE cells. ZC performed all single-channel experiments.

KSR provided information on missense variants found in the CF population.

JH and EJS designed studies for FRT cells and reviewed the manuscript.

DNS designed studies for single-channel experiments and reviewed the manuscript.

GRC was responsible for overall study design, development of the CFBE cell expression system, critical review of all results, and writing and editing the manuscript.

We thank the CFTR2 project for variant data, R.J. Bridges and CFFT for panels of small molecule CFTR potentiators and correctors, J.R. Riordan and CFFT for anti-CFTR antibodies, P. Thomas and L. Millen for N1303K cDNA construct used for single-channel studies, C.A. Cotton for identification of the L145H variant, M.J. Welsh for isogenic FRT cell lines, and F. Van Goor and Vertex Pharmaceuticals for access to ivacaftor response data generated using FRT cells.


Research Funding:

This work was supported by the NIH (R01DK44003), CF Foundation (Cuttin13A1, Cuttin15XX0, and Cuttin16IO to GRC; SORSCH13XX0 and SORSCH14XX0 to EJS), and CFFT (SHEPPA14XX0) to DNS.


  • Drug therapy
  • Genetic diseases
  • Genetics
  • Molecular genetics
  • Therapeutics

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

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Journal Title:

JCI insight


Volume 3, Number 14


, Pages e121159-e121159

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2018, American Society for Clinical Investigation

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