Nasal Epithelial Cell-Based Models for Individualized Study in Cystic Fibrosis

Keegan, Duncan E; Brewington, John J.

doi:10.3390/ijms22094448

Cited by 20 publications

(20 citation statements)

References 118 publications

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“…The use of primary, patient-derived nasal cultures in preclinical studies of CFTR modulators has been highly informative ( Keegan and Brewington, 2021 ; Laselva et al., 2021a , 2021b ; Oren et al., 2021 ; Park et al., 2020 ; Phuan et al., 2021 ; Veit et al., 2020 ). Interestingly, Amaral's group demonstrated a correlation between CFTR rescue by CFTR modulators in primary nasal epithelial cells and those in rectal organoids from the same individual ( Silva et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A new platform for high-throughput therapy testing on iPSC-derived lung progenitor cells from cystic fibrosis patients

et al. 2021

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For those people with cystic fibrosis carrying rare CFTR mutations not responding to currently available therapies, there is an unmet need for relevant tissue models for therapy development. Here, we describe a new testing platform that employs patient-specific induced pluripotent stem cells (iPSCs) differentiated to lung progenitor cells that can be studied using a dynamic, high-throughput fluorescence-based assay of CFTR channel activity. Our proof-of-concept studies support the potential use of this platform, together with a Canadian bioresource that contains iPSC lines and matched nasal cultures from people with rare mutations, to advance patient-oriented therapy development. Interventions identified in the high-throughput, stem cell-based model and validated in primary nasal cultures from the same person have the potential to be advanced as therapies.

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Section: Introductionmentioning

confidence: 99%

A new platform for high-throughput therapy testing on iPSC-derived lung progenitor cells from cystic fibrosis patients

et al. 2021

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“…Finally, we stress the suitability of an ex-vivo model for the functional characterization of rare mutations of the CFTR gene, or better, to predict the effect of molecular drugs independently by the CFTR genotype in the view of a personalized therapy [18]. Based on our data CF patients carrying F508del/unknown genetic profile would be eligible to Trikafta treatment.…”

Section: Discussionmentioning

confidence: 87%

Elexacaftor–Tezacaftor–Ivacaftor Therapy for Cystic Fibrosis Patients with the F508del/Unknown Genotype

Comegna¹,

Terlizzi²,

Salvatore³

et al. 2021

Preprint

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The new CFTR modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta) was approved by the FDA in October 2019 for treatment of Cystic Fibrosis in patients 12 years of age or older who have at least one F508del mutation in one allele and a minimal-function or another F508del mutation in the other allele. However, there is a group of patients, in addition to those with rare mutations, in which despite the presence of a F508del in one allele, it was not possible to identify any mutation in the other allele. Today these patients are excluded from treatment with Trikafta. In Italy CF patients carrying F508del/unknown represent about 3% (156 patients) of the overall Italian CF patients. In this paper we show that the Trikafta treatment of nasal epithelial cells, derived from F508del/Unknown patients, results in a significant rescue of CFTR activity. Based on our findings, we think that the F508del/Unknown patients considered in this study could obtain clinical benefits from Trikafta treatment, and we strongly suggest their eligibility for this type of treatment.This study, adding further evidence in the literature, once again confirms the validity of functional studies on nasal cells in the cystic fibrosis theratyping and personalized medicine.

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“…In this perspective, other novel therapies might also be studied in these 3D models, such as CRISPR-gene editing, read-through agents, or compounds targeting NMD. Indeed, theratyping using NEC cultures, either as ALI or organoids, is no longer limited to those subjects carrying rare, missense CFTR variants, as it is expanding to include nonsense mutations [48]. Moreover, although nasal spheroid/organoid cultures have been utilized for detecting viral infectivity [122], no study has investigated either viral or bacterial responses in the CF context.…”

Section: Discussionmentioning

confidence: 99%

“…Although a steady advancement in CFTR modulator therapy, the efficacy and safety of the approved drug for CF patients bearing rare mutations have not been evaluated. CFTR theratyping, i.e., the use of CFTR modulators to define defects in CFTR in vitro with patient-derived and tissue-based models, has the potential to identify novel CFTR modulators that could restore rare CFTR variants [48,49].…”

Section: In Vivo and In Vitro Models For Cfmentioning

confidence: 99%

Three-Dimensional Airway Spheroids and Organoids for Cystic Fibrosis Research

Laselva

Conese

2021

JoR

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Cystic fibrosis (CF) is an autosomal recessive multi-organ disease caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, with morbidity and mortality primacy related to the lung disease. The CFTR protein, a chloride/bicarbonate channel, is expressed at the apical side of airway epithelial cells and is mainly involved in appropriate ion and fluid transport across the epithelium. Although many animal and cellular models have been developed to study the pathophysiological consequences of the lack/dysfunction of CFTR, only the three-dimensional (3D) structures termed “spheroids” and “organoids” can enable the reconstruction of airway mucosa to model organ development, disease pathophysiology, and drug screening. Airway spheroids and organoids can be derived from different sources, including adult lungs and induced pluripotent stem cells (iPSCs), each with its advantages and limits. Here, we review the major features of airway spheroids and organoids, anticipating that their potential in the CF field has not been fully shown. Further work is mandatory to understand whether they can accomplish better outcomes than other culture conditions of airway epithelial cells for CF personalized therapies and tissue engineering aims.

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Nasal Epithelial Cell-Based Models for Individualized Study in Cystic Fibrosis

Cited by 20 publications

References 118 publications

A new platform for high-throughput therapy testing on iPSC-derived lung progenitor cells from cystic fibrosis patients

A new platform for high-throughput therapy testing on iPSC-derived lung progenitor cells from cystic fibrosis patients

Elexacaftor–Tezacaftor–Ivacaftor Therapy for Cystic Fibrosis Patients with the F508del/Unknown Genotype

Three-Dimensional Airway Spheroids and Organoids for Cystic Fibrosis Research

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