CFTR modulator theratyping: Current status, gaps and future directions

• Type of Material: Article
• Authors: John Paul Clancy, Cincinnati Children's Hospital Medical Center; Calvin U. Cotton, Case Western Reserve University; Scott H. Donaldson, University of North Carolina; George M. Solomon, University of Alabama Birmingham; Donald R. VanDevanter, Case Western Reserve University; Michael P. Boyle, Johns Hopkins University; Martina Gentzsch, University of North Carolina; Jerry A. Nick, National Jewish Health; Beate Illek, UCSF Benioff Childrens Hospital; John C. Wallenburg, Cystic Fibrosis Canada; Eric Sorscher, Emory University; Margarida D. Amaral, University of Lisbon; Jeffrey M. Beekman, University Medical Center Utrecht; Anjaparavanda P. Naren, Cincinnati Children's Hospital Medical Center; Robert J. Bridges, Chicago Medical School; Philip J. Thomas, University of Texas Southwestern; Garry Cutting, Johns Hopkins University; Steven Rowe, University of Alabama Birmingham; Anthony G. Durmowicz, Cystic Fibrosis Foundation; Martin Mense, Cyst Fibrosis Fdn; Kris D. Boeck, University Hospital Gasthuisberg; William Skach, Cystic Fibrosis Foundation; Christopher Penland, Cystic Fibrosis Foundation; Bruce Marshall, Cystic Fibrosis Foundation; Albert Faro, Cystic Fibrosis Foundation; Elizabeth Joseloff, Cystic Fibrosis Foundation; Hermann Bihler, Cystic Fibrosis Foundation; John Mahoney, Cystic Fibrosis Foundation; Drucy Borowitz, Cystic Fibrosis Foundation; Katherine L. Tuggle, Cystic Fibrosis Foundation
• Language: English
• Date: 2019-01-01
• Publisher: ELSEVIER SCIENCE BV
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jcf.2018.05.004
• Title of Journal or Parent Work: JOURNAL OF CYSTIC FIBROSIS
• Volume: 18
• Issue: 1
• Start Page: 22
• End Page: 34
• Grant/Funding Information: This workshop was funded by the Cystic Fibrosis Foundation
• Keywords: LUMACAFTOR-IVACAFTOR; TEZACAFTOR-IVACAFTOR; AGED 6-11 YEARS; CONDUCTANCE REGULATOR FUNCTION; CLINICAL-TRIAL; Science & Technology; Life Sciences & Biomedicine; Respiratory System; IN-VITRO; LONG-TERM EXPANSION; INTESTINAL ORGANOIDS; CYSTIC-FIBROSIS PATIENTS; SWEAT CHLORIDE
• Research Categories: Biology, Cell; Biology, Physiology

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.