The role of intestinal organoid function for evaluation of CFTR - PowerPoint PPT Presentation

Nov 14, 2022 •426 likes •630 views

The role of intestinal organoid function for evaluation of CFTR modulators Intestinal organoids for CF disease modeling Intestinal organoids for CF disease modeling Intestinal organoids for CF disease modeling Intestinal organoids for CF

The role of intestinal organoid function for evaluation of CFTR modulators
Intestinal organoids for CF disease modeling
Intestinal organoids for CF disease modeling
Intestinal organoids for CF disease modeling
Intestinal organoids for CF disease modeling
(Individual) drug efficacy + CFTR protein restoring drugs (VX770 / VX809) (Individual) efficacy Pharmacodynamics CFTR genotyping What does a drug do to a body? Ex vivo primary cells Pharmacokinetics What does a body do with a drug?
Benefits of organoid cell cultures - Rectal biopsy: relatively easily accessible (painless, w/o hemorroids) - Robust and ‘easy’ culture: ~250 donors (40 CFTR genotypes) - start of shipped biopsies within 3-4 days - self- organize - Stem cells: expansion and biobanking - New technology - Impact of ex vivo culture and culture components variability - Intestinal origin
Intestinal organoids Intestinal organoids Dekkers et al Nature Medicine, 2013 Dekkers et al . Rare Diseases, 2013
cAMP-driven fluid secretion in organoids is CFTR-dependent Forskolin / Cholera toxin + (cAMP ) Fluid transport
CFTR-directed therapy in organoids F508del / F508del + F508del / F508del CFTR directed therapy
CFTR function measurement: FIS
Typing a patient function using organoids 8 x 3: 24 wells 4 drug conditions (-,770, 809, 770+809) 96 wells: 1 plate
Organoid responses and FEV1 (published data)
Identifying potential responders
G1249R
CFTR biomarker response is very consistent
Airway parameters FEV1 RAW0.5
Pharmacokinetic parameter: VX770 in blood
Intestinal organoids and individual drug readout
Conclusions and Discussion Characterization of unknown genotypes (rare mutations) additional tool (preclinical / serum endpoint) standardization (shipping to central lab is possible) grey zone? Genotypes vs individuals exclude subjects from treatment? can we increase individual drug efficacy through dosaging? future: identify optimal combination? How to define a clinical responder? - relation between in vitro and in vivo CFTR biomarkers > (in vitro) CFTR biomarker and multi-origin disease phenotype - prophylactic treatments or not?

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