• Allison F McCague, Karen S Raraigh, Matthew J Pellicore, Emily F Davis-Marcisak, Taylor A Evans, Sangwoo T Han, Zhongzhou Lu, Anya T Joynt, Neeraj Sharma, Carlo Castellani, Joseph M Collaco, Mary Corey, Michelle H Lewis, Chris M Penland, Johanna M Rommens, Anne L Stephenson, Patrick R Sosnay, and Garry R Cutting.
• 1 McKusick-Nathans Institute of Genetic Medicine, School of Medicine.
• Am. J. Respir. Crit. Care Med. 2019 May 1; 199 (9): 1116-1126.

AbstractRationale: The advent of precision treatment for cystic fibrosis using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable to increases in cystic fibrosis transmembrane conductance regulator (CFTR) function. Objectives: To derive CFTR function of a variety of CFTR genotypes and correlate with key clinical features (sweat chloride concentration, pancreatic exocrine status, and lung function) to develop benchmarks for assessing response to CFTR modulators. Methods: CFTR function assigned to 226 unique CFTR genotypes was correlated with the clinical data of 54,671 individuals enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project. Cross-sectional FEV1% predicted measurements were plotted by age at which measurement was obtained. Shifts in sweat chloride concentration and lung function reported in CFTR modulator trials were compared with function-phenotype correlations to assess potential efficacy of therapies. Measurements and Main Results: CFTR genotype function exhibited a logarithmic relationship with each clinical feature. Modest increases in CFTR function related to differing genotypes were associated with clinically relevant improvements in cross-sectional FEV1% predicted over a range of ages (6-82 yr). Therapeutic responses to modulators corresponded closely to predictions from the CFTR2-derived relationship between CFTR genotype function and phenotype. Conclusions: Increasing CFTR function in individuals with severe disease will have a proportionally greater effect on outcomes than similar increases in CFTR function in individuals with mild disease and should reverse a substantial fraction of the disease process. This study provides reference standards for clinical outcomes that may be achieved by increasing CFTR function.

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