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Sci Transl Med. 2016 Jun 22;8(344):344ra84. doi: 10.1126/scitranslmed.aad8278.

Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.

Author information

1
Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands. Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
2
Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
3
Department of Gastroenterology and Hepatology, Erasmus University Medical Center, 3015 CE Rotterdam, Netherlands.
4
Department of Pediatric Pulmonology, Erasmus University Medical Center/Sophia Children's Hospital, 3015 CN Rotterdam, Netherlands.
5
Department of Pulmonology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
6
Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
7
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
8
Department of Pediatric Gastroenterology, Erasmus University Medical Center/Sophia Children's Hospital, 3015 CN Rotterdam, Netherlands.
9
Department of Clinical Chemistry, Erasmus University Medical Center/Sophia Children's Hospital, 3015 CN Rotterdam, Netherlands.
10
Department of Respiratory Medicine, Academic Medical Center, 1105 AZ Amsterdam, Netherlands.
11
Department of Pulmonology and Cystic Fibrosis, Haga Teaching Hospital, 2545 CH The Hague, Netherlands.
12
Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Center Utrecht, 3584 CT Utrecht, Netherlands.
13
Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands. Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands. Regenerative Medicine Center Utrecht, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands. j.beekman@umcutrecht.nl.

Abstract

Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.

PMID:
27334259
DOI:
10.1126/scitranslmed.aad8278
[Indexed for MEDLINE]

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