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Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR.
Am J Respir Crit Care Med. 2020 Jun 25 [Online ahead of print]AJ

Abstract

RATIONALE

Animal models have been highly informative for understanding characteristics, onset, and progression of cystic fibrosis (CF) lung disease. In particular, the CFTR-/- rat has revealed insights into the airway mucus defect characteristic of CF, but does not replicate a human-relevant CFTR variant.

OBJECTIVE

We hypothesized that a rat expressing a humanized version of CFTR, harboring the ivacaftor-sensitive variant G551D, could be used to test the impact of CFTR modulators on pathophysiologic development and correction.

METHODS

In this study, we describe a humanized-CFTR rat expressing the G551D variant, obtained by zinc finger nuclease editing of a human cDNA super-exon, spanning exon 2-27, with a 5' insertion site into the rat gene just beyond intron 1. This targeted insertion takes advantage of the endogenous rat promoter, resulting in appropriate expression compared to wild-type.

MEASUREMENTS AND MAIN RESULTS

The bioelectric phenotype of the epithelia recapitulates the expected absence of CFTR activity, which was restored with ivacaftor. Large airway defects, including depleted airway surface liquid and periciliary layers, delayed mucus transport rates, and increased mucus viscosity were normalized following administration of ivacaftor.

CONCLUSIONS

This model is useful to understand mechanisms of disease and the extent of pathology reversal with CFTR modulators.

Authors+Show Affiliations

University of Alabama at Birmingham, Medicine, Cystic Fibrosis Center, Birmingham, Alabama, United States; susanbirket@uabmc.edu.The University of Alabama at Birmingham Department of Medicine, 164494, Birmingham, Alabama, United States.The University of Alabama at Birmingham Department of Medicine, 164494, Birmingham, Alabama, United States.The University of Alabama at Birmingham Department of Medicine, 164494, Birmingham, Alabama, United States.University of Alabama at Birmingham, Medicine, Birmingham, Alabama, United States.University of Alabama at Birmingham, Department of Medicine, The Gregory Fleming James Cystic Fibrosis Research Center, Birmingham, Alabama, United States.University of Alabama at Birmingham, Cystic Fibrosis Center, Birmingham, Alabama, United States.Emory University, 1371, Atlanta, Georgia, United States.University of Alabama at Birmingham, Cellular, Developmental and Integrative Biology and Department of Pediatrics, Birmingham, Alabama, United States.Horizon Discovery Group plc, 394549, St. Louis, Missouri, United States.Horizon Discovery Group PLC, St. Louis, Missouri, United States.Horizon Discovery Group plc, 394549, St. Louis, Missouri, United States.Massachusetts General Hospital - Harvard Medical School Center for Nervous System Repair, 273161, Wellman Center for Photomedicine, Harvard MIT Division of Health Sciences and Technology, Boston, Massachusetts, United States.Emory University, 1371, Atlanta, Georgia, United States.University of Alabama at Birmingham, Medicine, Birmingham, Alabama, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32584141

Citation

Birket, Susan E., et al. "Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR." American Journal of Respiratory and Critical Care Medicine, 2020.
Birket SE, Davis JM, Fernandez-Petty CM, et al. Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR. Am J Respir Crit Care Med. 2020.
Birket, S. E., Davis, J. M., Fernandez-Petty, C. M., Henderson, A. G., Oden, A. M., Tang, L., Wen, H., Hong, J., Fu, L., Chambers, A., Fields, A., Zhao, G., Tearney, G. J., Sorscher, E. J., & Rowe, S. M. (2020). Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR. American Journal of Respiratory and Critical Care Medicine. https://doi.org/10.1164/rccm.202002-0369OC
Birket SE, et al. Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR. Am J Respir Crit Care Med. 2020 Jun 25; PubMed PMID: 32584141.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR. AU - Birket,Susan E, AU - Davis,Joy M, AU - Fernandez-Petty,Courtney M, AU - Henderson,Alexander G, AU - Oden,Ashley M, AU - Tang,LiPing, AU - Wen,Hui, AU - Hong,Jeong, AU - Fu,Lianwu, AU - Chambers,Andre, AU - Fields,Alvin, AU - Zhao,Gojun, AU - Tearney,Guillermo J, AU - Sorscher,Eric J, AU - Rowe,Steven M, Y1 - 2020/06/25/ PY - 2020/6/26/entrez KW - G551D KW - cystic fibrosis KW - ivacaftor KW - mucus KW - rat model JF - American journal of respiratory and critical care medicine JO - Am. J. Respir. Crit. Care Med. N2 - RATIONALE: Animal models have been highly informative for understanding characteristics, onset, and progression of cystic fibrosis (CF) lung disease. In particular, the CFTR-/- rat has revealed insights into the airway mucus defect characteristic of CF, but does not replicate a human-relevant CFTR variant. OBJECTIVE: We hypothesized that a rat expressing a humanized version of CFTR, harboring the ivacaftor-sensitive variant G551D, could be used to test the impact of CFTR modulators on pathophysiologic development and correction. METHODS: In this study, we describe a humanized-CFTR rat expressing the G551D variant, obtained by zinc finger nuclease editing of a human cDNA super-exon, spanning exon 2-27, with a 5' insertion site into the rat gene just beyond intron 1. This targeted insertion takes advantage of the endogenous rat promoter, resulting in appropriate expression compared to wild-type. MEASUREMENTS AND MAIN RESULTS: The bioelectric phenotype of the epithelia recapitulates the expected absence of CFTR activity, which was restored with ivacaftor. Large airway defects, including depleted airway surface liquid and periciliary layers, delayed mucus transport rates, and increased mucus viscosity were normalized following administration of ivacaftor. CONCLUSIONS: This model is useful to understand mechanisms of disease and the extent of pathology reversal with CFTR modulators. SN - 1535-4970 UR - https://www.unboundmedicine.com/medline/citation/32584141/Ivacaftor_Reverses_Airway_Mucus_Abnormalities_in_a_Rat_Model_Harboring_a_Humanized_G551D-CFTR L2 - https://www.atsjournals.org/doi/10.1164/rccm.202002-0369OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -
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