Human Primary Epithelial Cell Models: Promising Tools in the Era of Cystic Fibrosis Personalized Medicine

Awatade, Nikhil T; Wong, Sharon L.; Hewson, Chris; Fawcett, Laura K.; Kicic, Anthony; Jaffé, Adam; Waters, Shafagh A.

doi:10.3389/fphar.2018.01429

Cited by 72 publications

(75 citation statements)

References 76 publications

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“…Primary, reprogrammed and engineered human cell models have become important tools to identify novel pharmacotherapies. The effects of certain therapies may also be exploited at an individual level in ex vivo patient-derived specimens, such as primary bronchial/nasal epithelial cells, and intestinal/respiratory organoids (Fulcher and Randell, 2013;Dekkers et al, 2016a;Dekkers et al, 2016b;Pranke et al, 2017;Awatade et al, 2018;Brewington et al, 2018;Chen et al, 2018;Berkers et al, 2019;Merket et al, 2019). As these cell models recapitulate several features of the parental organ, they are useful to understand the impact of genetic factors on individual disease and predict clinical efficacy of therapies.…”

Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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“…Additionally, CRAEC can be seeded from co-culture into air-liquid interface culture (ALI) to form a differentiated pseudostratified epithelial layer (128,129). This has enabled many CF research groups to look to CF primary airway epithelial cell models in order to understand the cellular drivers of progressive lung disease, and more recently to evaluate the efficacy of CFTR modulators in restoring CFTR function in target cells (130,131). Nasal pAEC are increasingly being used in epithelial CFTR studies, since their growth, differentiation, CFTR activity, and response to modulators are similar to lower airway cells, and have the advantage of being more readily accessible (129).…”

Section: Primary Airway Epithelial Cellsmentioning

confidence: 99%

Progress in Model Systems of Cystic Fibrosis Mucosal Inflammation to Understand Aberrant Neutrophil Activity

2020

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In response to recurrent infection in cystic fibrosis (CF), powerful innate immune signals trigger polymorphonuclear neutrophil recruitment into the airway lumen. Exaggerated neutrophil proteolytic activity results in sustained inflammation and scarring of the airways. Consequently, neutrophils and their secretions are reliable clinical biomarkers of lung disease progression. As neutrophils are required to clear infection and yet a direct cause of airway damage, modulating adverse neutrophil activity while preserving their pathogen fighting function remains a key area of CF research. The factors that drive their pathological behavior are still under investigation, especially in early disease when aberrant neutrophil behavior first becomes evident. Here we examine the latest findings of neutrophils in pediatric CF lung disease and proposed mechanisms of their pathogenicity. Highlighted in this review are current and emerging experimental methods for assessing CF mucosal immunity and human neutrophil function in the laboratory.

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“…Patient-derived primary human bronchial epithelial (hBE) cells cultured at the air-liquid interface are a clinically relevant model of a pseudostratified airway epithelium, with detectable cilia beating and airway surface liquid, as well as measurable CFTR function that correlates well with spirometry measures in patients (FEV1). 16 Thus, we next tested ASO effects in this model. As these cells form tight monolayers, we first confirmed ASO delivery through use of the RNaseH1 ASO to knockdown CFTR (Figure S6).…”

Section: Asos Increase Defective Cftr In Combination With Correctors mentioning

confidence: 99%

Steric Inhibition of 5′ UTR Regulatory Elements Results in Upregulation of Human CFTR

et al. 2019

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Cystic fibrosis (CF) is an autosomal recessive monogenic disease caused by mutations in the CFTR gene. Therapeutic approaches that are focused on correcting CFTR protein face the challenge of the heterogeneity in CFTR mutations and resulting defects. Thus, while several small molecules directed at CFTR show benefit in the clinic for subsets of CF patients, these drugs cannot treat all CF patients. Additionally, the clinical benefit from treatment with these modulators could be enhanced with novel therapies. To address this unmet need, we utilized an approach to increase CFTR protein levels through antisense oligonucleotide (ASO)mediated steric inhibition of 5 0 UTR regulatory elements. We identified ASOs to upregulate CFTR protein expression and confirmed the regulatory role of the sites amenable to ASO-mediated upregulation. Two ASOs were investigated further, and both increased CFTR protein expression and function in cell lines and primary human bronchial epithelial cells with distinct CF genotypes. ASO treatment further increased CFTR function in almost all CF genotypes tested on top of treatment with the FDA approved drug Symdeko (ivacaftor and tezacaftor). Thus, we present a novel approach to CFTR therapeutic intervention, through ASO-mediated modulation of translation.

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Human Primary Epithelial Cell Models: Promising Tools in the Era of Cystic Fibrosis Personalized Medicine

Cited by 72 publications

References 76 publications

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Progress in Model Systems of Cystic Fibrosis Mucosal Inflammation to Understand Aberrant Neutrophil Activity

Steric Inhibition of 5′ UTR Regulatory Elements Results in Upregulation of Human CFTR

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