FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes

• Published in: Journal of cystic fibrosis Vol. 22; no. 3; pp. 548 - 559
• Main Authors: de Poel, E., Spelier, S., Hagemeijer, M.C., van Mourik, P., Suen, S.W.F., Vonk, A.M., Brunsveld, J.E., Ithakisiou, G.N., Kruisselbrink, E., Oppelaar, H., Berkers, G., de Winter de Groot, K.M., Heida-Michel, S., Jans, S.R., van Panhuis, H., Bakker, M., van der Meer, R., Roukema, J., Dompeling, E., Weersink, E.J.M., Koppelman, G.H., Blaazer, A.R., Muijlwijk-Koezen, J.E., van der Ent, C.K., Beekman, J.M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2023
• Subjects: CFTR modulators; Colforsin; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - therapeutic use; Drug Evaluation, Preclinical; Drug Repositioning; Drug screening; Genotype; Humans; Mutation; Organoids; PDE4 inhibitors; Phosphodiesterase 4 Inhibitors - therapeutic use; Rare mutations; Rare mutations; Organoids; Drug screening; PDE4 inhibitors; CFTR modulators
• ISSN: 1569-1993; 1873-5010
• DOI: 10.1016/j.jcf.2023.03.004

•We implemented a high-throughput 384-wells version of the functional FIS assay to screen a large number of PDIOs for compounds that enhance CFTR function.•We found that PDE4 inhibitors are potent CFTR function inducers when residual CFTR function is either present or created by additional compound exposure.•We show that CFTR modulators can be beneficial for CF patients with CFTR mutations that are not eligible for CFTR modulators at present-day.•Our study demonstrates how preclinical studies using PDIOs can be used to initiate drug repurposing efforts, paving the way for patient stratification in the upcoming era of personalized medicine. 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 who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF. We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators. In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy. This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies. 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.