Alpha-1-antitrypsin (SERPINA1) (A1AT)

Alpha-1-antitrypsin (A1AT), encoded by the SERPINA1 gene, is a critical serine protease inhibitor (serpin) primarily synthesized in the liver and secreted into the systemic circulation [1]. Its principal physiological function is to neutralize neutrophil elastase in the lungs, thereby protecting the delicate alveolar architecture from proteolytic damage and maintaining respiratory integrity [1, 2]. Genetic mutations in the SERPINA1 gene, most commonly the PiZ variant, result in Alpha-1 antitrypsin deficiency (AATD), a condition characterized by the misfolding and polymerization of the protein within the endoplasmic reticulum of hepatocytes [3, 4]. This leads to a dual disease state: pulmonary emphysema due to a lack of circulating A1AT to protect the lungs, and progressive liver disease, including cirrhosis and hepatocellular carcinoma, due to the toxic accumulation of protein polymers in the liver [4, 5]. Current clinical management involves augmentation therapy with plasma-derived A1AT to slow lung tissue loss, while next-generation therapies like RNA interference (RNAi) and CRISPR-based genomic editing are being developed to address the underlying genetic cause and reduce hepatic proteotoxicity [6, 7]. Sources: [1] UniProt P01009; [2] NCBI Gene 5265; [3] ATS/ERS Statement (2003); [4] StatPearls: Alpha-1 Antitrypsin Deficiency; [5] Nature Reviews Disease Primers (2016); [6] ClinicalTrials.gov NCT04561713; [7] Beam Therapeutics Pipeline.

Other names

Alpha-1 protease inhibitorAlpha-1-antitrypsinSerpin A1A1ATPIAAT

Augmentation of serum alpha-1 antitrypsin levels; RNA interference-mediated degradation of SERPINA1 mRNA; CRISPR-based genomic correction of the SERPINA1 gene mutation.