CFTR modulator theratyping: Current status, gaps and future directions

被引：200

作者：

Clancy, John Paul ^{[1
]}

Cotton, Calvin U. ^{[2
]}

Donaldson, Scott H. ^{[3
]}

Solomon, George M. ^{[4
]}

VanDevanter, Donald R. ^{[5
]}

Boyle, Michael P. ^{[6
]}

Gentzsch, Martina ^{[7
,19
]}

Nick, Jerry A. ^{[8
]}

Illek, Beate ^{[9
]}

Wallenburg, John C. ^{[10
]}

Sorscher, Eric J. ^{[11
]}

Amaral, Margarida D. ^{[12
]}

Beekman, Jeffrey M. ^{[13
]}

Naren, Anjaparavanda P. ^{[1
]}

Bridges, Robert J. ^{[14
]}

Thomas, Philip J. ^{[15
]}

Cutting, Garry ^{[16
]}

Rowe, Steven ^{[4
]}

Durmowicz, Anthony G. ^{[17
]}

Mense, Martin ^{[17
]}

Boeck, Kris D. ^{[18
]}

Skach, William ^{[17
]}

Penland, Christopher ^{[17
]}

Joseloff, Elizabeth ^{[17
]}

Bihler, Hermann ^{[17
]}

Mahoney, John ^{[17
]}

Borowitz, Drucy ^{[17
]}

Tuggle, Katherine L. ^{[17
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA

[2] Case Western Reserve Univ, Cleveland, OH 44106 USA

[3] Univ N Carolina, Marsico Lung Inst, Chapel Hill, NC 27515 USA

[4] Univ Alabama Birmingham, Birmingham, AL USA

[5] Case Western Reserve Univ, Sch Med, Cleveland, OH USA

[6] Johns Hopkins Univ, Cyst Fibrosis Fdn, Baltimore, MD 21218 USA

[7] Univ N Carolina, Marsico Lung Inst, Cyst Fibrosis Res Ctr, Chapel Hill, NC 27515 USA

[8] Natl Jewish Hlth, Denver, CO USA

[9] UCSF Benioff Childrens Hosp Oakland, Oakland, CA USA

[10] Cyst Firbosis Canada, Fibrose Kyst, Toronto, ON, Canada

[11] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA

[12] Univ Lisbon, Lisbon, Portugal

[13] Univ Med Ctr Utrecht, Utrecht, Netherlands

[14] Chicago Med Sch, N Chicago, IL USA

[15] UT Southwestern, Dallas, TX USA

[16] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA

[17] Cyst Fibrosis Fdn, Bethesda, MD USA

[18] Univ Hosp Gasthuisberg, Leuven, Belgium

[19] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27515 USA

来源：

JOURNAL OF CYSTIC FIBROSIS | 2019年 / 18卷 / 01期

关键词：

CYSTIC-FIBROSIS PATIENTS; LONG-TERM EXPANSION; CONDUCTANCE REGULATOR FUNCTION; AGED; 6-11; YEARS; IN-VITRO; TEZACAFTOR-IVACAFTOR; INTESTINAL ORGANOIDS; LUMACAFTOR-IVACAFTOR; SWEAT CHLORIDE; CLINICAL-TRIAL;

D O I：

10.1016/j.jcf.2018.05.004

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

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. (C) 2018 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

引用

页码：22 / 34

页数：13

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