TY - JOUR
T1 - Pharmacological analysis of CFTR variants of cystic fibrosis using stem cell-derived organoids
AU - Chen, Kevin G.
AU - Zhong, Pingyu
AU - Zheng, Wei
AU - Beekman, Jeffrey M.
N1 - Funding Information:
This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) at the National Institute of Neurological Disorders and Stroke (K.G.C.) and, in part, by the Singapore Immunology Network (P.Z.) and the Dutch Cystic Fibrosis Foundation (NCFS) (J.M.B.). Author contributions were as follows: conception or design of the work (K.G.C. and P.Z.); acquisition or analysis or interpretation of data for the work (K.G.C., W.Z., and J.M.B.); drafting the work or revising it critically for important intellectual content (K.G.C., P.Z., and W.Z.); final approval of the version to be published (K.G.C. and J.M.B.); and agreement to be accountable for all aspects of the work (K.G.C., P.Z., W.Z., and J.M.B.). We are grateful to anonymous reviewers for their insightful comments and constructive suggestions. We would like to thank Michael Gottesman, Pamela Robey, and Barbara Mallon for support of this work; Michael Dean and Richard Leapman for critical reading of this manuscript; and Judith Welsh, NIH Library Editing Service, for reviewing the manuscript.
Funding Information:
This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) at the National Institute of Neurological Disorders and Stroke (K.G.C.) and, in part, by the Singapore Immunology Network (P.Z.) and the Dutch Cystic Fibrosis Foundation (NCFS) (J.M.B.). Author contributions were as follows: conception or design of the work (K.G.C. and P.Z.); acquisition or analysis or interpretation of data for the work (K.G.C. W.Z. and J.M.B.); drafting the work or revising it critically for important intellectual content (K.G.C. P.Z. and W.Z.); final approval of the version to be published (K.G.C. and J.M.B.); and agreement to be accountable for all aspects of the work (K.G.C. P.Z. W.Z. and J.M.B.). We are grateful to anonymous reviewers for their insightful comments and constructive suggestions. We would like to thank Michael Gottesman, Pamela Robey, and Barbara Mallon for support of this work; Michael Dean and Richard Leapman for critical reading of this manuscript; and Judith Welsh, NIH Library Editing Service, for reviewing the manuscript.
Publisher Copyright:
© 2019
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Cystic fibrosis (CF) is a life-shortening genetic disease caused by mutations of CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator. Despite considerable progress in CF therapies, targeting specific CFTR genotypes based on small molecules has been hindered because of the substantial genetic heterogeneity of CFTR mutations in patients with CF, which is difficult to assess by animal models in vivo. There are broadly four classes (e.g., II, III, and IV) of CF genotypes that differentially respond to current CF drugs (e.g., VX-770 and VX-809). In this review, we shed light on the pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.
AB - Cystic fibrosis (CF) is a life-shortening genetic disease caused by mutations of CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator. Despite considerable progress in CF therapies, targeting specific CFTR genotypes based on small molecules has been hindered because of the substantial genetic heterogeneity of CFTR mutations in patients with CF, which is difficult to assess by animal models in vivo. There are broadly four classes (e.g., II, III, and IV) of CF genotypes that differentially respond to current CF drugs (e.g., VX-770 and VX-809). In this review, we shed light on the pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.
UR - http://www.scopus.com/inward/record.url?scp=85067309835&partnerID=8YFLogxK
U2 - 10.1016/j.drudis.2019.05.029
DO - 10.1016/j.drudis.2019.05.029
M3 - Review article
C2 - 31173911
AN - SCOPUS:85067309835
SN - 1359-6446
VL - 24
SP - 2126
EP - 2138
JO - Drug Discovery Today
JF - Drug Discovery Today
IS - 11
ER -