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 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 this therapy. CONCLUSION: 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. 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.

Forskolin induced swelling (FIS) assay in intestinal organoids to guide eligibility for compassionate use treatment in a CF patient with a rare genotype.

BACKGROUND: Forskolin-induced swelling of patient-derived organoids has been used to measure patient-specific CFTR function and CFTR modulator response. We present a case where CFTR function assessment in intestinal organoids was decisive for a patients' acceptance to a compassionate use program. CASE DESCRIPTION: A 56 years old female with cystic fibrosis compound heterozygous for F508del and a rare CFTR allele (c.3717+5G>T) experienced rapid clinical deterioration. The forskolin-induced swelling assay on her rectal organoids was used to confirm that the rare mutation is a minimal residual function mutation, and that other CFTR modulators would not likely be effective. Based on these two criteria and her clinical status, she was accepted for compassionate use of elexacaftor/tezacaftor/ivacaftor and showed improvement in all clinical parameters. CONCLUSIONS: This reports describes a first example that intestinal organoids were used to identify a previously unknown CFTR mutation as a minimal function mutation. The individual FIS-based definition of minimal residual function, response to ele/tez/iva and/or lack of response to other CFTR modulating drugs, may thus provide a tool for access to ele/tez/iva treatment for people with rare genotypes.