期刊
JOURNAL OF CYSTIC FIBROSIS
卷 17, 期 1, 页码 26-33出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jcf.2017.06.010
关键词
CFTR; Organoid; Modulator; Personalized model system
资金
- Cystic Fibrosis Foundation Therapeutics [CLANCY14XX0]
- Cystic Fibrosis Foundation [CLANCY15R0]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [K25HL125954] Funding Source: NIH RePORTER
Background: Expansion of CFTR modulators to patients with rare/undescribed mutations will be facilitated by patient-derived models quantifying CFTR function and restoration. We aimed to generate a personalized model system of CFTR function and modulation using non-surgically obtained nasal epithelial cells (NECs). Methods: NECs obtained by curettage from healthy volunteers and CF patients were expanded and grown in 3-dimensional culture as spheroids, characterized, and stimulated with cAMP-inducing agents to activate CFTR. Spheroid swelling was quantified as a proxy for CFTR function. Results: NEC spheroids recapitulated characteristics of pseudostratified respiratory epithelia. When stimulated with forskolin/IBMX, spheroids swelled in the presence of functional CFTR, and shrank in its absence. Spheroid swelling quantified mutant CFTR restoration in F508del homozygous cells using clinically available CFTR modulators. Conclusions : NEC spheroids hold promise for understanding rare CFTR mutations and personalized modulator testing to drive evaluation for CF patients with common, rare or undescribed mutations. Portions-of this data have previously been presented in abstract form at the 2016 meetings of the American Thoracic Society and the 2016 North American Cystic Fibrosis Conference. (C) 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
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