FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes.
CFTR modulators
Drug screening
Organoids
PDE4 inhibitors
Rare mutations
Journal
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
ISSN: 1873-5010
Titre abrégé: J Cyst Fibros
Pays: Netherlands
ID NLM: 101128966
Informations de publication
Date de publication:
May 2023
May 2023
Historique:
received:
13
09
2022
revised:
06
01
2023
accepted:
03
03
2023
medline:
12
6
2023
pubmed:
6
5
2023
entrez:
5
5
2023
Statut:
ppublish
Résumé
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.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
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
UNASSIGNED
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.
Identifiants
pubmed: 37147251
pii: S1569-1993(23)00067-X
doi: 10.1016/j.jcf.2023.03.004
pii:
doi:
Substances chimiques
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
Phosphodiesterase 4 Inhibitors
0
Colforsin
1F7A44V6OU
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
548-559Informations de copyright
Copyright © 2023. Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Declaration of Competing Interest J.M.B. reports personal fees from Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries and Galapagos, outside the submitted work; In addition, J.M.B. has a patent(s) related to the FIS-assay with royalties paid. C.K.v.d.E. reports grants from GSK, grants from Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis, Galapagos NV and Eloxx outside the submitted work; In addition, C.K.v.d.E. has a patent 10006904 with royalties paid. G.H.K. reports grants from Lung Foundation of the Netherlands, Vertex Pharmaceuticals, UBBO EMMIUS foundation, GSK, TEVA the Netherlands, ZON-MW (Vici-grant), European Union (H2020), outside the submitted work; and he has participated in advisory boards meetings to GSK and PURE-IMS outside the submitted work (Money to institution). All other authors have nothing to disclose.