CFTR Rescue in Intestinal Organoids with GLPG/ABBV-2737, ABBV/GLPG-2222 and ABBV/GLPG-2451 Triple Therapy

Eyleen de Poel; Sacha Spelier; Ricardo Korporaal; Ka Wai Lai; Sylvia F Boj; Katja Conrath; Cornelis K van der Ent; Jeffrey M Beekman

doi:10.3389/fmolb.2021.698358

CFTR Rescue in Intestinal Organoids with GLPG/ABBV-2737, ABBV/GLPG-2222 and ABBV/GLPG-2451 Triple Therapy

Front Mol Biosci. 2021 Sep 15:8:698358. doi: 10.3389/fmolb.2021.698358. eCollection 2021.

Authors

Eyleen de Poel^{1

2}, Sacha Spelier^{1

2}, Ricardo Korporaal³, Ka Wai Lai³, Sylvia F Boj³, Katja Conrath⁴, Cornelis K van der Ent¹, Jeffrey M Beekman^{1

2}

Affiliations

¹ Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, Utrecht, Netherlands.
² Regenerative Medicine Utrecht, University Medical Center, Utrecht University, Utrecht, Netherlands.
³ Hubrecht Organoid Technology (HUB), Utrecht, Netherlands.
⁴ Galapagos NV, Mechelen, Belgium.

Abstract

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.

Keywords: CFTR; CFTR modulator therapy; F508del; cystic fibrosis; forskolin induced swelling assay; intestinal organoids; personalized medicine.