FDA-Approved Drug Screening in Patient-Derived Organoids Demonstrates Potential of Drug Repurposing for Rare Cystic Fibrosis Genotypes

Background Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF, but a large unmet need remains to identify new treatments for all pwCF. Methods We used 76 non-homozygous F508del-CFTR PDIOs to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. Results Based on the results of a secondary validation screen, we investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators in further detail. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs and that CFTR modulator treatment rescues of CF genotypes that are currently not eligible for this therapy. Conclusions This study exemplifies the feasibility of high-throughput compound screening using PDIOs and we show the potential of repurposing drugs for pwCF that are currently not eligible for therapies. One-sentence Summary We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.

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