(642) CFTR Rescue in Intestinal Organoids with FT Triple Combination in Comparison to Trikafta

Background: Trikafta (elexacaftor/tezacaftor/ivacaftor), the highly effective CFTR modulator combination from Vertex has received both FDA and EMA approval for the treatment of CF patients harboring at least one F508del mutation in the CFTR gene. Unfortunately, this modulator combination is very expensive and therefore unavailable to many CF patients who might benefit from it. The development of alternative CFTR modulators is therefore interesting. One of these alternatives include the triple modulator combination by Fair Therapeutics (FT), consisting of a CFTR corrector (posenacaftor), potentiator (dirocaftor) and mRNA amplifier (nesolicaftor). In this project, intestinal organoids derived from patients either eligible for Trikafta or harboring rare CFTR mutations will be screened for functional CFTR restoration upon Trikafta or FT triple combination treatment. We aim to identify CFTR mutations non-eligible for Trikafta that do respond to Trikafta treatment and to identify CFTR mutations that respond to the FT triple modulator combination.

Methods: Intestinal organoids derived from CF patients eligible for Trikafta or harboring rare mutations will be screened for functional CFTR restoration after Trikafta or FT triple combination treatment. CFTR function will be assessed using the forskolin-induced swelling (FIS) assay and Western blots will be performed to detect CFTR protein restoration.

Results: For this study 90 intestinal organoids derived from CF patients have been selected from our organoid biobank. 45 of these intestinal organoids harbor either F508Del/F508Del or F508Del/minimal function mutations, whereas the other 45 harbor rare mutations. The measurements for this screen are still ongoing.

Conclusions: This project is still in progress. However, preliminary data does show promising results for the FT triple combination treatment.

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