Serpin family A member 1 (SERPINA1) (SERPINA1)

The Serpin family A member 1 (SERPINA1) gene encodes Alpha-1 antitrypsin (AAT), a critical serine protease inhibitor primarily synthesized in hepatocytes [1, 2]. In patients with Alpha-1 antitrypsin deficiency (AATD), mutations such as the PiZ allele (Glu342Lys) cause the AAT protein to misfold and form toxic polymers within the endoplasmic reticulum of hepatocytes [1, 5]. This accumulation results in a gain-of-toxic-function leading to liver cirrhosis and hepatocellular carcinoma, while the resulting deficiency of circulating AAT causes a loss-of-function leading to pulmonary emphysema [2, 5]. Targeting the genomic DNA of SERPINA1 in hepatocytes using gene-editing technologies like CRISPR/Cas9 or base editors aims to permanently correct the mutation or silence the mutant allele [3, 4]. Investigational therapies such as BEAM-302 and NTLA-3001 utilize lipid nanoparticles to deliver editing machinery directly to the liver to address the genetic root of the disease [3, 4]. By modifying the genomic sequence directly within the liver, these treatments offer a potential one-time curative solution for both the hepatic and pulmonary manifestations of AATD [5].

Other names

Alpha-1 antitrypsin geneAATA1ATPIAlpha-1-antiproteinaseSerpin A1

Direct modification of the SERPINA1 genomic sequence via CRISPR/Cas9 or base editing to correct the PiZ mutation or disrupt mutant protein production [3, 4].