Alpha-1 antitrypsin (AAT) (AAT)

Alpha-1 antitrypsin is a member of the serpin superfamily of protease inhibitors, primarily synthesized in the liver and secreted into the systemic circulation [UniProt Consortium, 2023]. Its principal biological function is the inhibition of neutrophil elastase in the lower respiratory tract, thereby protecting the delicate alveolar extracellular matrix from proteolytic degradation during inflammatory responses [StatPearls, 2022]. Genetic mutations in the SERPINA1 gene, most notably the PiZ variant, lead to Alpha-1 antitrypsin deficiency (AATD), a condition characterized by both a loss-of-function in the lungs and a toxic gain-of-function in the liver [NIH, 2023]. In the liver, misfolded AAT proteins polymerize and accumulate within hepatocytes, causing cellular stress and potentially leading to cirrhosis or hepatocellular carcinoma [StatPearls, 2022]. Therapeutic interventions traditionally involve augmentation therapy with plasma-derived AAT to prevent lung destruction, while modern investigational approaches utilize RNA interference to reduce hepatic production of the mutant protein or small molecule chaperones to improve protein folding and secretion [FDA, 2023; Takeda, 2023].

Other names

Alpha-1-proteinase inhibitorSerpin A1SERPINA1PIA1AT

Augmentation therapy restores serum levels of the protein to inhibit neutrophil elastase; RNA interference (RNAi) silences the SERPINA1 gene to reduce toxic protein accumulation in the liver; small molecule chaperones promote proper folding of mutant AAT [StatPearls, 2022; Takeda, 2023].