Animal and model systems for studying cystic fibrosis

Abstract

The cystic fibrosis (CF) field is the beneficiary of five species of animal models that lack functional cystic fibrosis transmembrane conductance regulator (CFTR) channel. These models are rapidly informing mechanisms of disease pathogenesis and CFTR function regardless of how faithfully a given organ reproduces the human CF phenotype. New approaches of genetic engineering with RNA-guided nucleases are rapidly expanding both the potential types of models available and the approaches to correct the CFTR defect. The application of new CRISPR/Cas9 genome editing techniques are similarly increasing capabilities for in vitro modeling of CFTR functions in cell lines and primary cells using air-liquid interface cultures and organoids. Gene editing of CFTR mutations in somatic stem cells and induced pluripotent stem cells is also transforming gene therapy approaches for CF. This short review evaluates several areas that are key to building animal and cell systems capable of modeling CF disease and testing potential treatments.

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

“…CF knockout animals, including mice, rats, rabbits, ferrets, and pigs, have been produced which recapitulate human CF disease with varying degrees of faithfulness [62]. Further, other models of CF lung disease such as the βENaC-transgenic mouse have also been useful for preclinical studies of CF [23,26].…”

Inflammation and host-pathogen interaction: Cause and consequence in cystic fibrosis lung disease

“…CF is the first human genetic disease to benefit from the directed engineering of several different species of animal models defective for the Cftr gene (mice, pigs, ferrets, rats, rabbit and, more recently, sheep), and one additional modelthe Scnn1b-Tg mice -with airway-specific overexpression of the βENaC subunit as an alternative approach to mimic CF ion transport pathophysiology in the lung [10,35,37,38]. Each of these models and their comparisons can assist our understanding of the mechanisms behind the exacerbated inflammation and infection in CF lungs.…”

Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets

“…The development of CF pig and ferret models has provided new opportunities to interrogate the links between infection and inflammation in the CF lung (11)(12)(13). In both of these CF models, the lungs are rapidly colonized by bacteria within weeks to months (14,15).…”