John Paul Clancy1, Calvin U Cotton2, Scott H Donaldson3, George M Solomon4, Donald R VanDevanter5, Michael P Boyle6, Martina Gentzsch7, Jerry A Nick8, Beate Illek9, John C Wallenburg10, Eric J Sorscher11, Margarida D Amaral12, Jeffrey M Beekman13, Anjaparavanda P Naren14, Robert J Bridges15, Philip J Thomas16, Garry Cutting17, Steven Rowe4, Anthony G Durmowicz18, Martin Mense18, Kris D Boeck19, William Skach18, Christopher Penland18, Elizabeth Joseloff18, Hermann Bihler18, John Mahoney18, Drucy Borowitz18, Katherine L Tuggle18. 1. Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. Electronic address: john.clancy@cchmc.org. 2. Case Western Reserve University, United States. 3. University of North Carolina at Chapel Hill - Marsico Lung Institute, United States. 4. University of Alabama at Birmingham, University of Alabama at Birmingham. 5. Case Western Reserve University School of Medicine, Cleveland, OH, United States. 6. Cystic Fibrosis Foundation, Johns Hopkins University, United States. 7. Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, United States; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, United States. 8. National Jewish Health, Denver, CO, United States. 9. UCSF Benioff Children's Hospital Oakland, United States. 10. Cystic Firbosis Canada, Directeur en chef des activites scientifiques, fibrose kystique, Canada. 11. Emory University Department of Pediatrics, United States. 12. University of Lisboa, Portugal. 13. University Medical Center Utrecht, Utrecht, the Netherlands. 14. Cincinnati Children's Hospital Medical Center, United States. 15. Chicago Medical School, United States. 16. UT Southwestern, United States. 17. Johns Hopkins University School of Medicine, United States. 18. Cystic Fibrosis Foundation, United States. 19. University Hospital Gasthuisberg, Belgium.
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.
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 CFpatients, 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 CFpatients. 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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