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

TY - JOUR

T1 - Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis

AU - Dekkers, Johanna F

AU - Berkers, Gitte

AU - Kruisselbrink, Evelien

AU - Vonk, Annelotte

AU - de Jonge, Hugo R

AU - Janssens, Hettie M

AU - Bronsveld, Inez

AU - van de Graaf, Eduard A

AU - Nieuwenhuis, Edward E S

AU - Houwen, Roderick H J

AU - Vleggaar, Frank P

AU - Escher, Johanna C

AU - de Rijke, Yolanda B

AU - Majoor, Christof J

AU - Heijerman, Harry G M

AU - de Winter-de Groot, Karin M

AU - Clevers, Hans

AU - van der Ent, Cornelis K

AU - Beekman, Jeffrey M

N1 - Copyright © 2016, American Association for the Advancement of Science.

PY - 2016/6/22

Y1 - 2016/6/22

N2 - 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.

AB - 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.

U2 - 10.1126/scitranslmed.aad8278

DO - 10.1126/scitranslmed.aad8278

M3 - Article

C2 - 27334259

SN - 1946-6234

VL - 8

SP - 344ra84

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 344

ER -