Correlating cystic fibrosis transmembrane conductance regulator function with clinical features to inform precision treatment of cystic fibrosis

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, Michael Collaco, Mary Corey, Michelle H. Lewis, Chris M. Penland, Johanna M. Rommens, Anne L. Stephenson, Patrick Ryan Sosnay, Garry R Cutting

Research output: Contribution to journalArticle

Abstract

Rationale: 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 FEV 1 % 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 FEV 1 % 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.

Original languageEnglish (US)
Pages (from-to)1116-1126
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume199
Issue number9
DOIs
StatePublished - May 1 2019

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Cystic Fibrosis Transmembrane Conductance Regulator
Cystic Fibrosis
Genotype
Sweat
Chlorides
Benchmarking
Lung

Keywords

  • Cystic fibrosis transmembrane conductance regulator modulator
  • Genotype–phenotype
  • Lung function
  • Sweat chloride

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Correlating cystic fibrosis transmembrane conductance regulator function with clinical features to inform precision treatment of cystic fibrosis. / McCague, Allison F.; Raraigh, Karen S.; Pellicore, Matthew J.; Davis-Marcisak, Emily F.; Evans, Taylor A.; Han, Sangwoo T.; Lu, Zhongzhou; Joynt, Anya T.; Sharma, Neeraj; Castellani, Carlo; Collaco, Michael; Corey, Mary; Lewis, Michelle H.; Penland, Chris M.; Rommens, Johanna M.; Stephenson, Anne L.; Sosnay, Patrick Ryan; Cutting, Garry R.

In: American journal of respiratory and critical care medicine, Vol. 199, No. 9, 01.05.2019, p. 1116-1126.

Research output: Contribution to journalArticle

McCague, AF, Raraigh, KS, Pellicore, MJ, Davis-Marcisak, EF, Evans, TA, Han, ST, Lu, Z, Joynt, AT, Sharma, N, Castellani, C, Collaco, M, Corey, M, Lewis, MH, Penland, CM, Rommens, JM, Stephenson, AL, Sosnay, PR & Cutting, GR 2019, 'Correlating cystic fibrosis transmembrane conductance regulator function with clinical features to inform precision treatment of cystic fibrosis', American journal of respiratory and critical care medicine, vol. 199, no. 9, pp. 1116-1126. https://doi.org/10.1164/rccm.201901-0145OC
McCague, Allison F. ; Raraigh, Karen S. ; Pellicore, Matthew J. ; Davis-Marcisak, Emily F. ; Evans, Taylor A. ; Han, Sangwoo T. ; Lu, Zhongzhou ; Joynt, Anya T. ; Sharma, Neeraj ; Castellani, Carlo ; Collaco, Michael ; Corey, Mary ; Lewis, Michelle H. ; Penland, Chris M. ; Rommens, Johanna M. ; Stephenson, Anne L. ; Sosnay, Patrick Ryan ; Cutting, Garry R. / Correlating cystic fibrosis transmembrane conductance regulator function with clinical features to inform precision treatment of cystic fibrosis. In: American journal of respiratory and critical care medicine. 2019 ; Vol. 199, No. 9. pp. 1116-1126.
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abstract = "Rationale: 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 FEV 1 {\%} 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 FEV 1 {\%} 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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AU - Raraigh, Karen S.

AU - Pellicore, Matthew J.

AU - Davis-Marcisak, Emily F.

AU - Evans, Taylor A.

AU - Han, Sangwoo T.

AU - Lu, Zhongzhou

AU - Joynt, Anya T.

AU - Sharma, Neeraj

AU - Castellani, Carlo

AU - Collaco, Michael

AU - Corey, Mary

AU - Lewis, Michelle H.

AU - Penland, Chris M.

AU - Rommens, Johanna M.

AU - Stephenson, Anne L.

AU - Sosnay, Patrick Ryan

AU - Cutting, Garry R

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N2 - Rationale: 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 FEV 1 % 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 FEV 1 % 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.

AB - Rationale: 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 FEV 1 % 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 FEV 1 % 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.

KW - Cystic fibrosis transmembrane conductance regulator modulator

KW - Genotype–phenotype

KW - Lung function

KW - Sweat chloride

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