Figure 3.

Characterization of I37R-CFTR functional response to dual potentiator or corrector therapy or corrector(s)-potentiator(s) co-therapy in intestinal organoids

Forskolin-induced swelling (FIS) assay in organoids from participants with F508del/F508del (n = 5), G551D/F508del (n = 2), and I37R/F508del (n = 1) CFTR genotypes.

(A and B) Organoids were incubated overnight with 0.03% DMSO (untreated) or 3 μM VX-809 or 3 μM VX-661 or 3 μM VX-445 + 18 μM VX-661. After 24 h, organoids were stimulated with fsk ranging in concentration from 0.02 to 5 μM, either alone or in combination with a single potentiator (3 μM VX-770 or 3 μM G1837 or 50 μM Gen) or dual potentiators (VX-770 + G1837 or VX-770 + Gen or G1837 + Gen). FIS of organoids at 0.128uM fsk stimulated with VX-770, GLPG1837 (G1837), or genistein (Gen) or their combinations, following (A) 24 h pre-incubation with DMSO (untreated) or (B) corrector (VX-809 or VX-661), respectively.

(C) FIS of organoids at 0.128uM fsk stimulated without or with VX-770, following 24 h pre-incubation with dual correctors (VX-445+VX-661). Data corrected for baseline FIS and represented as violin plots with mean to show distribution. One-way analysis of variance (ANOVA) was used to determine statistical differences except in (C) where unpaired t test was used. ∗p < 0.05, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001