Personalized Medicine Based on Nasal Epithelial Cells: Comparative Studies with Rectal Biopsies and Intestinal Organoids

Silva, Iris; Railean, Violeta; Duarte, Aires; Amaral, Margarida D.

doi:10.3390/jpm11050421

Cited by 19 publications

(13 citation statements)

References 53 publications

(81 reference statements)

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“…Influential papers by Dekkers et al. ( Berkers et al., 2019 ; Fawcett et al., 2021 ; Ramalho et al., 2021 ; Silva et al., 2020 , 2021 ) highlighted the potential for the rectal organoid model to facilitate drug development and precision medicine for CF. Stem cells in the rectal mucosa provide a renewable source of this tissue, and biobanks of intestinal organoids from CF populations have been created around the world to enhance CF therapy development.…”

Section: Introductionmentioning

confidence: 99%

“…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 ). There are several published accounts of the use of nasal cultures in validating the relative efficacy of the new modulator combination in TRIKAFTA for rescuing F508del-CFTR and certain rare mutations ( Laselva et al., 2021a ; Veit et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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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%

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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“…Patients carrying the P67L- and L206W-CFTR mutations could benefit from the VX-661 + VX-445 corrector combination, which is so far not marketed separately, but may not necessarily profit from the addition of VX-770. This study adds to the growing number of publications, in which patient-derived HNE are used to study the modulator responses of rare CFTR mutants [ 27 , 31 , 32 , 33 , 58 , 59 , 60 , 61 , 62 ]. Our results suggest that HNE can not only be used to identify modulator responsive mutants, but also to optimize the modulator combinations for rare mutants.…”

Section: Discussionmentioning

confidence: 99%

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants

Veit

Velkov

et al. 2021

JPM

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Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.

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“…Pranke et al showed that CFTR chloride channel responses observed in patient-derived nasal epithelial cultures correlated with individual's improvement in Forced Expiratory Volume in the 1st second (FEV 1 ), i.e., the gold standard outcome to measure drug efficacy, measured after the treatment with a combination of Ivacaftor and the CFTR corrector Lumacaftor (Orkambi) [71,77]. Moreover, Amaral's group demonstrated a correlation between CFTR rescue by CFTR modulators in primary nasal epithelial cells and rectal organoids from the same individual [78].…”

Section: Airway Spheroids From Primary Airway Epithelial Cellsmentioning

confidence: 96%

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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Personalized Medicine Based on Nasal Epithelial Cells: Comparative Studies with Rectal Biopsies and Intestinal Organoids

Cited by 19 publications

References 53 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

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants

Three-Dimensional Airway Spheroids and Organoids for Cystic Fibrosis Research

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