CFTR modulator theratyping: Current status, gaps and future directions

John Paul Clancy, Calvin U. Cotton, Scott H. Donaldson, George M. Solomon, Donald R. VanDevanter, Michael P. Boyle, Martina Gentzsch, Jerry A. Nick, Beate Illek, John C. Wallenburg, Eric J. Sorscher, Margarida D. Amaral, Jeffrey M. Beekman, Anjaparavanda P. Naren, Robert J. Bridges, Philip J. Thomas, Garry Cutting, Steven Rowe, Anthony G. Durmowicz, Martin MenseKris D. Boeck, William Skach, Christopher Penland, Elizabeth Joseloff, Hermann Bihler, John Mahoney, Drucy Borowitz, Katherine L. Tuggle

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: New drugs that improve the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with discreet disease-causing variants have been successfully developed for cystic fibrosis (CF) patients. Preclinical model systems have played a critical role in this process, and have the potential to inform researchers and CF healthcare providers regarding the nature of defects in rare CFTR variants, and to potentially support use of modulator therapies in new populations. Methods: The Cystic Fibrosis Foundation (CFF) assembled a workshop of international experts to discuss the use of preclinical model systems to examine the nature of CF-causing variants in CFTR and the role of in vitro CFTR modulator testing to inform in vivo modulator use. The theme of the workshop was centered on CFTR theratyping, a term that encompasses the use of CFTR modulators to define defects in CFTR in vitro, with application to both common and rare CFTR variants. Results: Several preclinical model systems were identified in various stages of maturity, ranging from the expression of CFTR variant cDNA in stable cell lines to examination of cells derived from CF patients, including the gastrointestinal tract, the respiratory tree, and the blood. Common themes included the ongoing need for standardization, validation, and defining the predictive capacity of data derived from model systems to estimate clinical outcomes from modulator-treated CF patients. Conclusions: CFTR modulator theratyping is a novel and rapidly evolving field that has the potential to identify rare CFTR variants that are responsive to approved drugs or drugs in development.

Original languageEnglish (US)
JournalJournal of Cystic Fibrosis
DOIs
StateAccepted/In press - Jan 1 2018

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Cystic Fibrosis Transmembrane Conductance Regulator
Cystic Fibrosis
Direction compound
Pharmaceutical Preparations
Education
Health Personnel
Gastrointestinal Tract
Complementary DNA
Research Personnel

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pulmonary and Respiratory Medicine

Cite this

Clancy, J. P., Cotton, C. U., Donaldson, S. H., Solomon, G. M., VanDevanter, D. R., Boyle, M. P., ... Tuggle, K. L. (Accepted/In press). CFTR modulator theratyping: Current status, gaps and future directions. Journal of Cystic Fibrosis. https://doi.org/10.1016/j.jcf.2018.05.004

CFTR modulator theratyping : Current status, gaps and future directions. / Clancy, John Paul; Cotton, Calvin U.; Donaldson, Scott H.; Solomon, George M.; VanDevanter, Donald R.; Boyle, Michael P.; Gentzsch, Martina; Nick, Jerry A.; Illek, Beate; Wallenburg, John C.; Sorscher, Eric J.; Amaral, Margarida D.; Beekman, Jeffrey M.; Naren, Anjaparavanda P.; Bridges, Robert J.; Thomas, Philip J.; Cutting, Garry; Rowe, Steven; Durmowicz, Anthony G.; Mense, Martin; Boeck, Kris D.; Skach, William; Penland, Christopher; Joseloff, Elizabeth; Bihler, Hermann; Mahoney, John; Borowitz, Drucy; Tuggle, Katherine L.

In: Journal of Cystic Fibrosis, 01.01.2018.

Research output: Contribution to journalArticle

Clancy, JP, Cotton, CU, Donaldson, SH, Solomon, GM, VanDevanter, DR, Boyle, MP, Gentzsch, M, Nick, JA, Illek, B, Wallenburg, JC, Sorscher, EJ, Amaral, MD, Beekman, JM, Naren, AP, Bridges, RJ, Thomas, PJ, Cutting, G, Rowe, S, Durmowicz, AG, Mense, M, Boeck, KD, Skach, W, Penland, C, Joseloff, E, Bihler, H, Mahoney, J, Borowitz, D & Tuggle, KL 2018, 'CFTR modulator theratyping: Current status, gaps and future directions', Journal of Cystic Fibrosis. https://doi.org/10.1016/j.jcf.2018.05.004
Clancy JP, Cotton CU, Donaldson SH, Solomon GM, VanDevanter DR, Boyle MP et al. CFTR modulator theratyping: Current status, gaps and future directions. Journal of Cystic Fibrosis. 2018 Jan 1. https://doi.org/10.1016/j.jcf.2018.05.004
Clancy, John Paul ; Cotton, Calvin U. ; Donaldson, Scott H. ; Solomon, George M. ; VanDevanter, Donald R. ; Boyle, Michael P. ; Gentzsch, Martina ; Nick, Jerry A. ; Illek, Beate ; Wallenburg, John C. ; Sorscher, Eric J. ; Amaral, Margarida D. ; Beekman, Jeffrey M. ; Naren, Anjaparavanda P. ; Bridges, Robert J. ; Thomas, Philip J. ; Cutting, Garry ; Rowe, Steven ; Durmowicz, Anthony G. ; Mense, Martin ; Boeck, Kris D. ; Skach, William ; Penland, Christopher ; Joseloff, Elizabeth ; Bihler, Hermann ; Mahoney, John ; Borowitz, Drucy ; Tuggle, Katherine L. / CFTR modulator theratyping : Current status, gaps and future directions. In: Journal of Cystic Fibrosis. 2018.
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abstract = "Background: New drugs that improve the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with discreet disease-causing variants have been successfully developed for cystic fibrosis (CF) patients. Preclinical model systems have played a critical role in this process, and have the potential to inform researchers and CF healthcare providers regarding the nature of defects in rare CFTR variants, and to potentially support use of modulator therapies in new populations. Methods: The Cystic Fibrosis Foundation (CFF) assembled a workshop of international experts to discuss the use of preclinical model systems to examine the nature of CF-causing variants in CFTR and the role of in vitro CFTR modulator testing to inform in vivo modulator use. The theme of the workshop was centered on CFTR theratyping, a term that encompasses the use of CFTR modulators to define defects in CFTR in vitro, with application to both common and rare CFTR variants. Results: Several preclinical model systems were identified in various stages of maturity, ranging from the expression of CFTR variant cDNA in stable cell lines to examination of cells derived from CF patients, including the gastrointestinal tract, the respiratory tree, and the blood. Common themes included the ongoing need for standardization, validation, and defining the predictive capacity of data derived from model systems to estimate clinical outcomes from modulator-treated CF patients. Conclusions: CFTR modulator theratyping is a novel and rapidly evolving field that has the potential to identify rare CFTR variants that are responsive to approved drugs or drugs in development.",
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AU - Clancy, John Paul

AU - Cotton, Calvin U.

AU - Donaldson, Scott H.

AU - Solomon, George M.

AU - VanDevanter, Donald R.

AU - Boyle, Michael P.

AU - Gentzsch, Martina

AU - Nick, Jerry A.

AU - Illek, Beate

AU - Wallenburg, John C.

AU - Sorscher, Eric J.

AU - Amaral, Margarida D.

AU - Beekman, Jeffrey M.

AU - Naren, Anjaparavanda P.

AU - Bridges, Robert J.

AU - Thomas, Philip J.

AU - Cutting, Garry

AU - Rowe, Steven

AU - Durmowicz, Anthony G.

AU - Mense, Martin

AU - Boeck, Kris D.

AU - Skach, William

AU - Penland, Christopher

AU - Joseloff, Elizabeth

AU - Bihler, Hermann

AU - Mahoney, John

AU - Borowitz, Drucy

AU - Tuggle, Katherine L.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: New drugs that improve the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with discreet disease-causing variants have been successfully developed for cystic fibrosis (CF) patients. Preclinical model systems have played a critical role in this process, and have the potential to inform researchers and CF healthcare providers regarding the nature of defects in rare CFTR variants, and to potentially support use of modulator therapies in new populations. Methods: The Cystic Fibrosis Foundation (CFF) assembled a workshop of international experts to discuss the use of preclinical model systems to examine the nature of CF-causing variants in CFTR and the role of in vitro CFTR modulator testing to inform in vivo modulator use. The theme of the workshop was centered on CFTR theratyping, a term that encompasses the use of CFTR modulators to define defects in CFTR in vitro, with application to both common and rare CFTR variants. Results: Several preclinical model systems were identified in various stages of maturity, ranging from the expression of CFTR variant cDNA in stable cell lines to examination of cells derived from CF patients, including the gastrointestinal tract, the respiratory tree, and the blood. Common themes included the ongoing need for standardization, validation, and defining the predictive capacity of data derived from model systems to estimate clinical outcomes from modulator-treated CF patients. Conclusions: CFTR modulator theratyping is a novel and rapidly evolving field that has the potential to identify rare CFTR variants that are responsive to approved drugs or drugs in development.

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