Cystic fibrosis cell models for high-throughput analysis and drug screening.

Autor: Liu A; Department of Bioengineering, Rice University, Houston, Texas 77030, USA., Chokshi M; Department of Bioengineering, Rice University, Houston, Texas 77030, USA., Nguyen N; Institute of Biosciences and Technology, Texas A&M University, Houston, Texas, 77030, USA., Powell RT; Institute of Biosciences and Technology, Texas A&M University, Houston, Texas, 77030, USA., Stephan CC; Institute of Biosciences and Technology, Texas A&M University, Houston, Texas, 77030, USA., Bao G; Department of Bioengineering, Rice University, Houston, Texas 77030, USA. Electronic address: gang.bao@rice.edu.
Jazyk: angličtina
Zdroj: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society [J Cyst Fibros] 2024 Jul; Vol. 23 (4), pp. 716-724. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1016/j.jcf.2024.07.001
Abstrakt: Cystic fibrosis (CF) is a single-gene disorder that affects the lung, digestive system, and other organs. Mutations in the CF transmembrane conductance regulator (CFTR) gene are classified into several classes based on their pathogenic mechanism and clinical severity. The distinct and heterogeneous clinical behavior of each CF class and the respective CFTR mutations have made the development of a durable therapy for all CF patients extremely challenging. While the FDA-approved drug elexacaftor/tezacaftor/ivacaftor (Trikafta) benefits CF patients carrying at least one F508del mutation in CFTR, it's not effective for many CF patients carrying a variety of other CFTR mutations. To establish a better understanding of CF pathophysiology and aid the development of novel therapeutics for different classes of CF patients, we have created four CF-mutation-specific cell models that recapitulate respectively four distinct CF classes and disease phenotypes, as confirmed by sequencing, CFTR mRNA and protein quantification. The channel function of each cell model was first validated using a well-established FLIPR (Fluorescent Imaging Plate Reader) membrane potential assay and then assessed by the YFP-based functional assay. Integrated with a halide-sensitive fluorescent reporter, these CF cell models can be used for high-throughput drug screening, as demonstrated by a proof-of-concept study using Trikafta. These cell models have the potential to advance CFTR mutation-specific therapies thus addressing the unmet needs of CF patients with rare mutations.
Competing Interests: Declaration of competing interest The authors certify that they have no conflict of interest concerning the subject matter described in the manuscript
(Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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