Alpha-1 antitrypsin deficiency (AATD) causes both lung disease (early emphysema) and, in some, liver disease from accumulation of misfolded Z-AAT protein — and emerging therapies are increasingly addressing the two problems separately. For the lung disease, intravenous augmentation therapy with pooled human AAT raises plasma levels above the protective threshold and slows emphysema progression, and remains the mainstay. The most novel development targets the liver: fazirsiran, an RNA-interference therapeutic, reduces hepatic production of the mutant Z-AAT protein — in a Phase 2 trial it cut liver Z-AAT by around 83% with histologic improvement and fibrosis regression in some patients — and it is advancing through Phase 3 for AATD-associated liver disease. Recombinant and inhaled AAT formulations, and gene- and RNA-editing approaches aiming to correct the underlying mutation, are in earlier development.
Further reading: fazirsiran for AATD liver disease (Strnad et al., NEJM 2022); augmentation therapy reviews (Miravitlles et al., 2023); gene-editing approaches (Erion et al., Chest 2025).