Characterization of Nasal Potential Difference in cftr Knockout and F508del-CFTR Mice

Saussereau, Emilie; Roussel, Delphine; Diallo, Siradiou; Debarbieux, Laurent; Edelman, Aleksander; Sermet‐Gaudelus, Isabelle

doi:10.1371/journal.pone.0057317

Cited by 15 publications

(15 citation statements)

References 29 publications

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“…All CF mice appear to exhibit reduced cAMP-mediated chloride secretion in the nasal epithelium, which is characteristic of human CF airways [22,25]. The hyperactivity of ENaC, a feature present in human CF nasal epithelium [48], is also observed in the nasal epithelium of most CF mouse models including knockout [49], CFTR ΔF508 [49,50] and CFTR G551D strains [51]. When amiloride (a drug that blocks ENaC-mediated sodium absorption) is perfused through the nasal epithelium of a CF mouse, a significant depolarisation response occurs, which is consistent with the presence of sodium hyperabsorption [21].…”

Section: Upper Airway and Tracheal Phenotype In Cf Micementioning

confidence: 96%

“…Present [48,[110][111][112] (has been contested [109]) Present in nasal epithelium [49][50][51] Absent in lower airways [25] Present in trachea [69] Absent in nasal and tracheal epithelium [4] Absent in trachea [86,87] Absent in nasal and tracheal epithelium [101] MUCUS OBSTRUCTION IN LOWER AIRWAYS Mucus plugging [113] Absent [15] Mucus plugging [69] Increased stored nasal mucus [4] and preliminary evidence of mucus plugging of submucosal glands in large airways [77,80] Mucus plugging [ Animal models will continue to play a fundamental role in furthering our understanding of CF. Along with the development of rapid and precise gene editing technologies such as CRISPR/Cas9 comes the potential for new species to be used as platforms for modelling CF, as well as modification of existing models by introduction of human-specific CFTR mutations.…”

Section: In Airwaysmentioning

confidence: 99%

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Airway disease phenotypes in animal models of cystic fibrosis

2018

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In humans, cystic fibrosis (CF) lung disease is characterised by chronic infection, inflammation, airway remodelling, and mucus obstruction. A lack of pulmonary manifestations in CF mouse models has hindered investigations of airway disease pathogenesis, as well as the development and testing of potential therapeutics. However, recently generated CF animal models including rat, ferret and pig models demonstrate a range of well characterised lung disease phenotypes with varying degrees of severity. This review discusses the airway phenotypes of currently available CF animal models and presents potential applications of each model in airway-related CF research.

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Section: Upper Airway and Tracheal Phenotype In Cf Micementioning

confidence: 96%

Section: In Airwaysmentioning

confidence: 99%

Airway disease phenotypes in animal models of cystic fibrosis

2018

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“…A protocol for nasal potential differences (NPD), a CFTR biomarker in humans, has been adapted for use in CF mice. 63,64 We demonstrated rescue of CFTR activity by NPD in the CF mouse nose after rAAV2/5 delivery of a shortened CFTR (CFTRΔR 49 ), lacking a portion of the regulatory domain, which retains regulated channel activity. 45 Also, other vectors, such as LVs or a gene editing nanoparticle formulation, could partially restore CFTR function in CF mice as measured by improvements in NPD.…”

Section: Andmentioning

confidence: 97%

“…Therefore, the mouse nose can be used as a read‐out for CFTR function. A protocol for nasal potential differences (NPD), a CFTR biomarker in humans, has been adapted for use in CF mice . We demonstrated rescue of CFTR activity by NPD in the CF mouse nose after rAAV2/5 delivery of a shortened CFTR (CFTRΔR), lacking a portion of the regulatory domain, which retains regulated channel activity .…”

Section: What Have Cf Mouse Models Taught Us About Gene Therapy?mentioning

confidence: 99%

Roadmap for an early gene therapy for cystic fibrosis airway disease

2017

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Gene therapy provides a mutation-independent approach to treat or even cure CF airway disease. To develop a clinical candidate for CF gene therapy, a thorough examination of preclinical efficacy in relevant cell and animal models is a prerequisite. For a long time, the CF field was struggling with a lack of appropriate animal models for CF airway pathology. Since 2008, many different and complementary animal models have been generated that develop hallmarks of CF airway disease, including the CF pig, ferret, and rat. With this, a new era has arisen that allows investigating the efficacy of gene therapy beyond molecular and electrophysiological end-points. Successful gene therapy most likely requires an appropriate time window. CF lung pathology progresses with age and therefore an early treatment would be beneficial to prevent irreversible damage. In that regard, newborn screening programs and prenatal diagnosis already provide a basis to facilitate future preventive gene-based treatment. If successful, gene therapy for CF airway disease would markedly reduce the treatment burden and improve life quality and life expectancy of CF patients.

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“…Nasal potential difference (NPD) is an established assay for demonstrating in vivo correction of CFTR-dependent Cltransport [125][126][127]. For many of these studies, vector was delivered nasally and the NPD was used as evidence of CFTR complementation.…”

Section: Functional Correctionmentioning

confidence: 99%

Integrating Viral and Nonviral Vectors for Cystic Fibrosis Gene Therapy in the Airways

Cooney¹,

McCray²,

Sinn³

2015

Cystic Fibrosis in the Light of New Research

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Abstract"n important goal for cystic fibrosis CF gene therapy is to achieve long-term functional correction. While many vector options have been evaluated, integrating vectors have the greatest potential to maintain stable expression over time without a requirement for repeated administration. In this chapter, we discuss the importance of correcting the appropriate cell types, options for integrating vectors, animal models for CF gene therapy, and clinically relevant endpoint measurements. Lentiviral vectors are a promising option for CF gene therapy, as they integrate into the host genome and persistently express a transgene of interest. "irway cell tropism can be conferred by pseudotyping. Nonviral vectors such as DN" transposons can also integrate into the genome. Recent advances in hybrid viral/transposon vector technology improve the ability to deliver transposons to the airways in vivo. Integrating vector technology and new animal models have allowed considerable progress toward the goal of using gene therapy to correct life-long genetic diseases such as CF.

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Characterization of Nasal Potential Difference in cftr Knockout and F508del-CFTR Mice

Cited by 15 publications

References 29 publications

Airway disease phenotypes in animal models of cystic fibrosis

Airway disease phenotypes in animal models of cystic fibrosis

Roadmap for an early gene therapy for cystic fibrosis airway disease

Integrating Viral and Nonviral Vectors for Cystic Fibrosis Gene Therapy in the Airways

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