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Forskolin-induced Swelling in Intestinal Organoids: An In Vitro Assay for Assessing Drug Response in Cystic Fibrosis Patients
Published on: February 11, 2017
Human Induced Lung Organoids: A Promising Tool for Cystic Fibrosis Drug Screening
Anna Demchenko1, Maxim Balyasin2,3, Aleksandra Nazarova1
1Laboratory of Genome Editing, Research Centre for Medical Genetics, Moskvorechye, 1, 115522 Moscow, Russia.
Abstract:
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. Currently, CFTR modulators are the most effective treatment for CF; however, they may not be suitable for all patients. A representative and convenient in vitro model is needed to screen therapeutic agents under development. This study, on the most common mutation, F508del, investigates the efficacy of human induced pluripotent stem cell-derived lung organoids (hiLOs) from NKX2.1+ lung progenitors and airway basal cells (hiBCs) as a 3D model for CFTR modulator response assessment by a forskolin-induced swelling assay. Weak swelling was observed for hiLOs from NKX2.1+ lung progenitors and hiBCs in response to modulators VX-770/VX-809 and VX-770/VX-661, whereas the VX-770/VX-661/VX-445 combination resulted in the highest swelling response, indicating superior CFTR function restoration. The ROC analysis of the FIS assay results revealed an optimal cutoff of 1.21, with 65.9% sensitivity and 71.8% specificity, and the predictive accuracy of the model was 76.4%. In addition, this study compared the response of hiLOs with the clinical response of patients to therapy and showed similar drug response dynamics. Thus, hiLOs can effectively model the CF pathology and predict patients' specific response to modulators.
Insights
Human induced pluripotent stem cell-derived lung organoids (hiLOs) effectively model cystic fibrosis (CF) by predicting patient responses to CFTR modulator therapies. This 3D model shows promise for drug screening and personalized medicine.
Area of Science:
- Regenerative Medicine
- Genetics and Genomics
- Pharmacology
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by CFTR gene mutations, with CFTR modulators being the primary treatment.
- Current treatments may not be effective for all CF patients, necessitating better in vitro models for drug development.
- The F508del mutation is the most common cause of CF, making it a critical target for therapeutic research.
Purpose of the Study:
- To evaluate human induced pluripotent stem cell-derived lung organoids (hiLOs) and airway basal cells (hiBCs) as a 3D in vitro model for assessing CFTR modulator efficacy.
- To investigate the response of these models to different CFTR modulator combinations, particularly for the F508del mutation.
- To compare the in vitro model's drug response predictions with actual patient clinical responses.
Main Methods:
- Generation of hiLOs and hiBCs from lung progenitors and airway basal cells, respectively.
- Utilizing a forskolin-induced swelling (FIS) assay to measure CFTR function in response to various CFTR modulators (VX-770/VX-809, VX-770/VX-661, VX-770/VX-661/VX-445).
- Performing Receiver Operating Characteristic (ROC) analysis to determine the sensitivity, specificity, and predictive accuracy of the FIS assay in the hiLO model.
Main Results:
- hiLOs and hiBCs showed minimal swelling with VX-770/VX-809 and VX-770/VX-661, but significant restoration of CFTR function with the VX-770/VX-661/VX-445 combination.
- The FIS assay demonstrated a predictive accuracy of 76.4% with an optimal cutoff of 1.21 (65.9% sensitivity, 71.8% specificity).
- The drug response dynamics observed in hiLOs closely mirrored the clinical responses of CF patients to CFTR modulator therapy.
Conclusions:
- hiLOs serve as a robust and predictive 3D in vitro model for evaluating CFTR modulator efficacy in cystic fibrosis.
- This model accurately reflects CF pathology and can predict individual patient responses to CFTR-targeted therapies.
- The findings support the use of hiLOs for screening novel therapeutic agents and advancing personalized medicine approaches for CF.
