Animal models of cystic fibrosis in the era of highly effective modulator therapies

Grubb, Barbara R.; Livraghi‐Butrico, Alessandra

doi:10.1016/j.coph.2022.102235

Cited by 9 publications

(7 citation statements)

References 132 publications

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“…Studies looking at the safety of drugs on developing foetuses (e.g., evidence of cataracts), and the drug transfer to the foetus via placenta and lactation, are all important areas that could be performed in a rat model ( Jain et al, 2022 ). The potential for utilising CFTR modulators in animal models offers a platform to effectively study therapeutic windows and the impact of disease progression, as well as biodistribution, drug metabolism, drug half-life and drug toxicity ( Sun et al, 2019 ; Grubb and Livraghi-Butrico, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of elexacaftor-tezacaftor-ivacaftor on nasal potential difference and lung function in Phe508del rats

Reyne,

Cmielewski,

McCarron

et al. 2024

Front. Pharmacol.

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Introduction:Phe508del is the most common cystic fibrosis transmembrane conductance regulator (CFTR) gene variant that results in the recessive genetic disorder cystic fibrosis (CF). The recent development of highly effective CFTR modulator therapies has led to significant health improvements in individuals with this mutation. While numerous animal models of CF exist, few have a CFTR mutation that is amenable to the triple combination therapy elexacaftor-tezacaftor-ivacaftor (ETI).Methods: To determine the responsiveness of Phe508del rats to ETI, a baseline nasal potential difference was measured. Subsequently, they received ETI daily for 14 days, after which post-treatment nasal potential difference, lung mechanics (via flexiVent) and lung ventilation (via X-ray Velocimetry) were assessed.Results: Chloride ion transport in nasal airways was restored in Phe508del rats treated with ETI, but neither lung mechanics nor ventilation were significantly altered.Discussion: These findings validate the usefulness of this rat model for future investigations of modulator therapy in CF.

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Section: Discussionmentioning

confidence: 99%

Effect of elexacaftor-tezacaftor-ivacaftor on nasal potential difference and lung function in Phe508del rats

Reyne,

Cmielewski,

McCarron

et al. 2024

Front. Pharmacol.

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“…CF is a muco-obstructive disease hallmarked by dysfunctional airway microanatomy and aberrant mucus physiology [ 2 , 3 ]. Current animal models used to study airway and mucus dysfunction in CF, such as the CF pig and CFTR −/− ferret, are costly and difficult to maintain [ 4 , 9 ]. More recently, the CFTR −/− rat model has provided a means to study CF animals with aberrant mucus physiology in a more accessible model of CF [ 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…There have been multiple models developed that more effectively recapitulate the CF mucus pathophysiology observed in humans such as the CF piglet [ 11 , 12 ] and CF ferret [ 13 ] models. Although these species have proven useful for studying mucus pathophysiology and to advance therapeutic strategies [ 9 , 12 , 14 ], they can be costly and difficult to maintain [ 4 ]. Acquisition of CF mucus not contaminated by secondary infection also remains a research priority and is difficult to address in small and medium sized animals and acquisition of sterile mucus is not viable in humans with chronic infection.…”

Section: Introductionmentioning

confidence: 99%

An ex vivo rat trachea model reveals abnormal airway physiology and a gland secretion defect in cystic fibrosis

Harris,

Easter,

Ren

et al. 2023

PLoS ONE

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Cystic fibrosis (CF) is a genetic disease hallmarked by aberrant ion transport that results in delayed mucus clearance, chronic infection, and progressive lung function decline. Several animal models have been developed to study the airway anatomy and mucus physiology in CF, but they are costly and difficult to maintain, making them less accessible for many applications. A more available CFTR−/− rat model has been developed and characterized to develop CF airway abnormalities, but consistent dosing of pharmacologic agents and longitudinal evaluation remain a challenge. In this study, we report the development and characterization of a novel ex vivo trachea model that utilizes both wild type (WT) and CFTR−/− rat tracheae cultured on a porcine gelatin matrix. Here we show that the ex vivo tracheae remain viable for weeks, maintain a CF disease phenotype that can be readily quantified, and respond to stimulation of mucus and fluid secretion by cholinergic stimulation. Furthermore, we show that ex vivo tracheae may be used for well-controlled pharmacological treatments, which are difficult to perform on freshly excised trachea or in vivo models with this degree of scrutiny. With improved interrogation possible with a durable trachea, we also established firm evidence of a gland secretion defect in CFTR−/− rat tracheae compared to WT controls. Finally, we demonstrate that the ex vivo tracheae can be used to generate high mucus protein yields for subsequent studies, which are currently limited by in vivo mucus collection techniques. Overall, this study suggests that the ex vivo trachea model is an effective, easy to set up culture model to study airway and mucus physiology.

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“…Additional animal studies also confirm that MCC improves with CFTR modulator therapy. For a current review of CF animal models in the era of HEMT, the reader is directed to [203]. With an improvement in the CFTR function, fluid and electrolyte transport across the airway epithelia is closer to normal function.…”

Section: Effects Of Cftr Modulators On Airway Mucus Inflammation and ...mentioning

confidence: 99%

Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators

Ribeiro

Higgs

Muhlebach

et al. 2023

IJMS

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Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators, a new series of therapeutics that correct and potentiate some classes of mutations of the CFTR, have provided a great therapeutic advantage to people with cystic fibrosis (pwCF). The main hindrances of the present CFTR modulators are related to their limitations in reducing chronic lung bacterial infection and inflammation, the main causes of pulmonary tissue damage and progressive respiratory insufficiency, particularly in adults with CF. Here, the most debated issues of the pulmonary bacterial infection and inflammatory processes in pwCF are revisited. Special attention is given to the mechanisms favoring the bacterial infection of pwCF, the progressive adaptation of Pseudomonas aeruginosa and its interplay with Staphylococcus aureus, the cross-talk among bacteria, the bronchial epithelial cells and the phagocytes of the host immune defenses. The most recent findings of the effect of CFTR modulators on bacterial infection and the inflammatory process are also presented to provide critical hints towards the identification of relevant therapeutic targets to overcome the respiratory pathology of pwCF.

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Animal models of cystic fibrosis in the era of highly effective modulator therapies

Cited by 9 publications

References 132 publications

Effect of elexacaftor-tezacaftor-ivacaftor on nasal potential difference and lung function in Phe508del rats

Effect of elexacaftor-tezacaftor-ivacaftor on nasal potential difference and lung function in Phe508del rats

An ex vivo rat trachea model reveals abnormal airway physiology and a gland secretion defect in cystic fibrosis

Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators

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