TY - JOUR
T1 - CFTR modulator theratyping
T2 - Current status, gaps and future directions
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.
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2019/1
Y1 - 2019/1
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.
AB - 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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U2 - 10.1016/j.jcf.2018.05.004
DO - 10.1016/j.jcf.2018.05.004
M3 - Review article
C2 - 29934203
AN - SCOPUS:85048798938
SN - 1569-1993
VL - 18
SP - 22
EP - 34
JO - Journal of Cystic Fibrosis
JF - Journal of Cystic Fibrosis
IS - 1
ER -