A multimodal iPSC platform for cystic fibrosis drug testing

Berical, Andrew; Re, Lee; Lu, Junjie; Beermann, Mary Lou; Suer, Jake A. Le; Mithal, Aditya; Thomas, Dylan C.; Ranallo, Nicole; Peasley, Megan; Stuffer, Alex; Bukis, K.; Seymour, Rebecca; Harrington, Jan; Coote, Kevin; Valley, H.; Hurley, Killian; McNally, Paul; Mostoslavsky, Gustavo; Mahoney, J.A.; Randell, Scott H.; Hawkins, Finn

doi:10.1038/s41467-022-31854-8

Cited by 14 publications

(10 citation statements)

References 68 publications

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“…Moreover, the iPSC model was used to test novel therapeutic strategies to restore nonsense mutations (i.e., W1282X) and splicing mutations (i.e., I1234V) on iPSC-derived lung progenitor cells [ 172 ], reinforcing that airway epithelial cells from CF iPSCs can be used as a preclinical tool for precision medicine. More recently, iPSCs from PwCF carrying class I-III mutations demonstrated to serve as multimodal platforms for drug screening by Ussing chamber measurements and FIS assay [ 173 ].…”

Section: Preclinical In Vitro Modelsmentioning

confidence: 99%

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

Silva¹,

Laselva

Lopes‐Pacheco

2022

JPM

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The development of preclinical in vitro models has provided significant progress to the studies of cystic fibrosis (CF), a frequently fatal monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Numerous cell lines were generated over the last 30 years and they have been instrumental not only in enhancing the understanding of CF pathological mechanisms but also in developing therapies targeting the underlying defects in CFTR mutations with further validation in patient-derived samples. Furthermore, recent advances toward precision medicine in CF have been made possible by optimizing protocols and establishing novel assays using human bronchial, nasal and rectal tissues, and by progressing from two-dimensional monocultures to more complex three-dimensional culture platforms. These models also enable to potentially predict clinical efficacy and responsiveness to CFTR modulator therapies at an individual level. In parallel, advanced systems, such as induced pluripotent stem cells and organ-on-a-chip, continue to be developed in order to more closely recapitulate human physiology for disease modeling and drug testing. In this review, we have highlighted novel and optimized cell models that are being used in CF research to develop novel CFTR-directed therapies (or alternative therapeutic interventions) and to expand the usage of existing modulator drugs to common and rare CF-causing mutations.

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Section: Preclinical In Vitro Modelsmentioning

confidence: 99%

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

Silva¹,

Laselva

Lopes‐Pacheco

2022

JPM

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“…A multimodal iPSC-derived organoid platform was generated for CF drug testing. This platform can be used to accelerate therapeutic development for CF caused by rare variants ( Berical et al, 2022 ). Sodium/glucose cotransporters were revealed as potential therapeutic targets for CF ( Hirai et al, 2022 ).…”

Section: Applications Of Organoid Technology In Lung Diseasesmentioning

confidence: 99%

Organoid technology and applications in lung diseases: Models, mechanism research and therapy opportunities

Chen

2022

Front. Bioeng. Biotechnol.

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The prevalency of lung disease has increased worldwide, especially in the aging population. It is essential to develop novel disease models, that are superior to traditional models. Organoids are three-dimensional (3D) in vitro structures that produce from self-organizing and differentiating stem cells, including pluripotent stem cells (PSCs) or adult stem cells (ASCs). They can recapitulate the in vivo cellular heterogeneity, genetic characteristics, structure, and functionality of original tissues. Drug responses of patient-derived organoids (PDOs) are consistent with that of patients, and show correlations with genetic alterations. Thus, organoids have proven to be valuable in studying the biology of disease, testing preclinical drugs and developing novel therapies. In recent years, organoids have been successfully applied in studies of a variety of lung diseases, such as lung cancer, influenza, cystic fibrosis, idiopathic pulmonary fibrosis, and the recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. In this review, we provide an update on the generation of organoid models for these diseases and their applications in basic and translational research, highlighting these signs of progress in pathogenesis study, drug screening, personalized medicine and immunotherapy. We also discuss the current limitations and future perspectives in organoid models of lung diseases.

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“…The tissue can be started from primary cells or cell lines. Moreover, in the last decade multiple protocols have demonstrated the ability to derive hAECs from induced Pluripotent Stem Cells (iPSCs) [1,2].…”

Section: Introductionmentioning

confidence: 99%

Assessing motile cilia coverage and beat frequency in mammalian in-vitro cell culture tissues

Fradique

Causa

Delahousse

et al. 2023

Preprint

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Cilia density, distribution and beating frequency are important parameters lung tissues, for example in diagnostics of Primary Ciliary Dyskinesia, and in the study of \emph{in vitro} models, e.g. derived from induced Pluripotent Stem Cells. Video microscopy can be used to characterise these parameters, but most tools available at the moment are limited in the type of information they can provide, usually only describing the ciliary beat frequency of very small areas, while requiring human intervention and training for their use. We propose a novel and open source method to fully characterise cilia beating frequency and motile cilia coverage in an automated fashion without user intervention. We demonstrate the ability to differentiate between different coverage densities, identifying even small patches of cilia in a larger field of view, and to fully characterise the cilia beating frequency of all moving areas. We also show that the method can be used to combine multiple fields of view to better describe a sample without relying on small pre-selected regions of interest. This is released with a simple graphical user interface for file handling, enabling a full analysis of individual fields of view in a few minutes on a typical personal computer.

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A multimodal iPSC platform for cystic fibrosis drug testing

Cited by 14 publications

References 68 publications

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

Organoid technology and applications in lung diseases: Models, mechanism research and therapy opportunities

Assessing motile cilia coverage and beat frequency in mammalian in-vitro cell culture tissues

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