Human Induced Lung Organoids: A Promising Tool for Cystic Fibrosis Drug Screening

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. © 2025 by the authors.

Авторы
Demchenko A. , Balyasin M. , Nazarova A. , Grigorieva O. , Panchuk I. , Kondrateva E. , Tabakov V. , Schagina O. , Amelina E. , Smirnikhina S.
Издательство
MDPI AG
Номер выпуска
2
Язык
Английский
Статус
Опубликовано
Номер
437
Том
26
Год
2025
Организации
  • 1 Laboratory of Genome Editing, Research Centre for Medical Genetics, Moskvorechye, 1, Moscow, 115522, Russian Federation
  • 2 Scientific and Educational Resource Center, Peoples’ Friendship University of Russia, Miklukho-Maklaya, 6, Moscow, 117198, Russian Federation
  • 3 Department of Cell Technology, Endocrinology Research Center, Dm. Ulyanova Str., 11, Moscow, 117292, Russian Federation
  • 4 Moscow Branch of the Biobank “All-Russian Collection of Biological Samples of Hereditary Diseases”, Research Centre for Medical Genetics, Moskvorechye, 1, Moscow, 115522, Russian Federation
  • 5 DNA-Diagnostics Laboratory, Research Centre for Medical Genetics, Moskvorechye, 1, Moscow, 115522, Russian Federation
  • 6 Laboratory of Cystic Fibrosis, Research Institute of Pulmonology, 11th Parkovaya Str., 32/4, Moscow, 105077, Russian Federation
Ключевые слова
airway basal cells; CFTR modulators; cystic fibrosis; forskolin-induced swelling assay; human induced pluripotent stem cells; lung organoids
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