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

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

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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.

Original languageEnglish (US)
JournalJCI Insight
Issue number14
StatePublished - Jul 26 2018


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

ASJC Scopus subject areas

  • Medicine(all)


Dive into the research topics of 'Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators'. Together they form a unique fingerprint.

Cite this