TY - JOUR
T1 - CFTR Rescue in Intestinal Organoids with GLPG/ABBV-2737, ABBV/GLPG-2222 and ABBV/GLPG-2451 Triple Therapy
AU - de Poel, Eyleen
AU - Spelier, Sacha
AU - Korporaal, Ricardo
AU - Lai, Ka Wai
AU - Boj, Sylvia F.
AU - Conrath, Katja
AU - van der Ent, Cornelis K.
AU - Beekman, Jeffrey M.
N1 - Funding Information:
This study is powered by Health ∼ Holland, Top Sector Life Sciences & Health. Health-Holland (40-41200-98-9296). Organoid experiments performed at HUB were funded by Galapagos.
Publisher Copyright:
© Copyright © 2021 de Poel, Spelier, Korporaal, Lai, Boj, Conrath, van der Ent and Beekman.
PY - 2021/9/15
Y1 - 2021/9/15
N2 - Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed the treatment of cystic fibrosis (CF) by targeting the basis of the disease. In particular, treatment regimen consisting of multiple compounds with complementary mechanisms of action have been shown to result in optimal efficacy. Here, we assessed the efficacy of combinations of the CFTR modulators ABBV/GLPG-2222, GLPG/ABBV-2737 and ABBV/GLPG-2451, and compared it to VX-770/VX-809 in 28 organoid lines heterozygous for F508del allele and a class I mutation and seven homozygous F508del organoid lines. The combination ABBV/GLPG-2222/ABBV-2737/ABBV/GLPG-2451 showed increased efficacy over VX-770/VX-809 for most organoids, despite considerable variation in efficacy between the different organoid cultures. These differences in CFTR restoration between organoids with comparable genotypes underline the relevance of continuing to optimize the ABBV/GLPG‐Triple therapy, as well as the in vitro characterization of efficacy in clinically relevant models.
AB - Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed the treatment of cystic fibrosis (CF) by targeting the basis of the disease. In particular, treatment regimen consisting of multiple compounds with complementary mechanisms of action have been shown to result in optimal efficacy. Here, we assessed the efficacy of combinations of the CFTR modulators ABBV/GLPG-2222, GLPG/ABBV-2737 and ABBV/GLPG-2451, and compared it to VX-770/VX-809 in 28 organoid lines heterozygous for F508del allele and a class I mutation and seven homozygous F508del organoid lines. The combination ABBV/GLPG-2222/ABBV-2737/ABBV/GLPG-2451 showed increased efficacy over VX-770/VX-809 for most organoids, despite considerable variation in efficacy between the different organoid cultures. These differences in CFTR restoration between organoids with comparable genotypes underline the relevance of continuing to optimize the ABBV/GLPG‐Triple therapy, as well as the in vitro characterization of efficacy in clinically relevant models.
KW - CFTR
KW - CFTR modulator therapy
KW - cystic fibrosis
KW - F508del
KW - forskolin induced swelling assay
KW - intestinal organoids
KW - personalized medicine
UR - http://www.scopus.com/inward/record.url?scp=85116239726&partnerID=8YFLogxK
U2 - 10.3389/fmolb.2021.698358
DO - 10.3389/fmolb.2021.698358
M3 - Article
AN - SCOPUS:85116239726
VL - 8
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
M1 - 698358
ER -