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

作者：Eyleen de Poel, Sacha Spelier, Marne C. Hagemeijer, Peter van Mourik, S.W.F. Suen, Annelotte M. Vonk, Jesse E. Brunsveld, Georgia N. Ithakisiou, Evelien Kruisselbrink, Hugo Oppelaar, Gitte Berkers, Kate Groot, Sabine Heida-Michel, S.R. Jans, H. van Panhuis, Marleen Bakker, Renske van der Meer, Jolt Roukema, Edward Dompeling, Els J.M. Weersink, Gerard H. Koppelman, Antoni R. Blaazer, J.E. Muijlwijk-Koezen, Cornelis Korstiaan van der Ent, Jeffrey Matthijn Beekman · 发表于：Journal of Cystic Fibrosis · 年份：2023 · DOI：10.1016/j.jcf.2023.03.004 · 被引用次数：46 · 研究领域：Cystic Fibrosis Research Advances、Immunodeficiency and Autoimmune Disorders、Phosphodiesterase function and regulation

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 who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF. METHODS: 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. RESULTS: 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 thi...