Novel Transgenic Humanized Alpha-1 Antitrypsin Deficiency Mouse Model on Murine SERPINA1 Null Background

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder caused by accumulation of misfolded -1 antitrypsin within hepatocytes. AATD patients are prone to develop liver disease that remains undiagnosed until the late stages of the disease. Due to challenges in manipulating the -1 antitrypsin genes in mice, determining a true loss of function of -1 antitrypsin in previous AATD mouse models has been challenging. Here, we report generation and liver characterization of a new humanized transgenic mouse model for AATD with a background of a CRISPR-Cas9 generated SERPINA1-null mouse. Male and female transgenic mice for normal (Pi*M) and mutant (Pi*Z) variants of human -1 antitrypsin at 4-6 months of age were subjected to this study. The accumulation of human -1 antitrypsin in the hepatocytes and fibrotic features of the liver were monitored by performing an in vivo study. We demonstrate a strong liver phenotype satisfying clinically relevant manifestations of liver pathology associated with AATD, including hepatic accumulation of human -1 antitrypsin globules, liver deposition of extracellular matrix proteins, hepatic ER stress, and liver fibrosis in Pi*Z mice, in addition to mild systemic inflammation. In addition to major phenotypic criteria of AATD-associated liver fibrosis, accompanying single-nucleus RNA-seq data demonstrate activation of pathways associated with liver metabolic changes, inflammation, and regeneration. Data from this study suggest our humanized transgenic AATD mouse model could provide a suitable model to study -1 antitrypsin loss of function, replicate the pathophysiology of AATD associated liver disease, and evaluate therapeutic reagents against this disease. NEW & NOTEWORTHYWe have characterized a new humanized transgenic mouse model of -1 antitrypsin deficiency with a SERPINA1-null background that shows strong manifestations of liver disease. Our data explores the altered phenotype of -1 antitrypsin deficient hepatocytes and suggests a relationship between liver cell types during disease progression. This model may become a useful tool for investigating -1 antitrypsin loss of function, pathogenic mechanisms, and for drug discovery aimed at both prevention and treatment of the disease.