These findings implicate mucoinflammatory processes in the CF lung as pathogenic in the absence of clinically apparent bacterial and fungal infections.

Cystic fibrosis (CF) is a multi-organ disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In patients with CF, abnormalities initiate in several organs prior to birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)-responsive CFTRG551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in pancreas, intestine, and male reproductive tract. Homozygous CFTRG551D/G551D animals showed the greatest VX-770-mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival and reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first two weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.

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.

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Alpha-1 antitrypsin (AAT) deficiency (AATD) is the most common genetic cause and risk factor for chronic obstructive pulmonary disease, but the field lacks a large animal model that allows for longitudinal assessment of pulmonary function. We hypothesized that ferrets would model human AATD-related lung and hepatic disease. AAT-knockout (AAT-KO) and PiZZ (E342K, the most common mutation in humans) ferrets were generated and compared to matched controls using custom-designed flexiVent modules to perform pulmonary function tests (PFTs), quantitative computed tomography (QCT), bronchoalveolar lavage (BAL) proteomics, and alveolar morphometry. Complete loss of AAT (AAT-KO) led to increased pulmonary compliance and expiratory airflow limitation, consistent with obstructive lung disease. QCT and morphometry confirmed emphysema and airspace enlargement, respectively. Pathway analysis of BAL proteomics data revealed inflammatory lung disease and impaired cellular migration. The PiZ mutation resulted in altered AAT protein folding in the liver, hepatic injury, reduced plasma concentrations of AAT, and PiZZ ferrets developed obstructive lung disease. In summary, AAT-KO and PiZZ ferrets model the progressive obstructive pulmonary disease seen in AAT-deficient patients and may serve as a platform for preclinical testing of therapeutics including gene therapy.

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by engineering a conditional activator [b-catenin lacking degradation sites; Catnb loxP(ex3) ], targeted to lung MPCs using ABCG2CreERT2 with reporters: Rosa26 m-tdTomato/mGFPlox-stop . This lineage-labeling mouse model, in the presence or absence of Wnt activation, was subjected to vascular injury using SUGEN 5416 and hypoxia. Physiological endpoints of vascular injury; morphometrics, including stereology to measure mean linear intercept (MLI); and lineage analysis were performed. Murine and human MPCs, normal and COPD, were isolated by flow cytometry and analyzed in vitro in coculture analysis with MVECs to define physiological relevance of the cell-cell interactions.Rationale: The most prevalent genetic cause of chronic obstructive pulmonary disease is alpha-1 antitrypsin (A1AT) deficiency, a disorder that has yet to be widely modeled in animals because of species-specific differences between rodents and humans.