Ferrets might be valuable animal models for longitudinal assessments of pulmonary function in alpha-1 antitrypsin deficiency (AATD) preclinical studies, according to the results of a new study published in JCI Insight.

The researchers generated 2 ferret models to mimic human AATD-related lung and hepatic disease: the alpha-1 antitrypsin (AAT)-knockout (AAT-KO) model and the PiZZ model (ie, a model with the E342K mutation in SERPINA1, the most frequent Z-allele mutation in humans).

“These two large animal models of AATD are valuable additions to the cadre of rodent models that have been developed through genetic or environmental means to reduce circulating AAT and develop emphysema,” the researchers said.

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AAT-KO ferrets presented with increased lung compliance, expiratory airflow limitation, and enlarged alveolar spaces. These manifestations were consistent with emphysema and obstructive lung disease.

The AAT-deficient PiZZ ferrets also developed obstructive lung disease. Moreover, the mutation of SERPINA1 led to altered AAT protein folding in the liver, hepatic injury, and reduced plasma concentrations of AAT (on average ~40% less AAT in the plasma as compared to controls).

“The PiZZ ferret model serves as a valuable addition to the AAT-KO model in that it develops hepatic injury consistent with that observed in human patients, and it allows for the study of both gene therapy and editing strategies in a relevant model of lung and liver disease,” the researchers said.

Lung compliance was found elevated at the youngest age analyzed, which suggested that the loss of AAT may affect humans at an early age, the authors said. Also, adolescent AATD ferrets already had signs of emphysema.

Male AAT-KO and PiZZ ferrets showed a greater increase in lung compliance and airflow obstruction when compared to females. Moreover, inflammatory insults led to increased airspace size and enhanced airflow obstruction in AAT-KO ferrets.


He N, Liu X, Vegter AR, et al. Ferret models of alpha-1 antitrypsin deficiency develop lung and liver disease. JCI Insight. Published online February 1, 2022. doi:10.1172/jci.insight.143004