Alpha-1 antitrypsin (SERPINA1) gene (E342K mutation) (SERPINA1 (E342K))

The SERPINA1 E342K genomic DNA target refers to the specific point mutation (Glu342Lys) in the alpha-1 antitrypsin gene located within the nuclei of hepatocytes (UniProt P01009). This mutation, commonly known as the Z allele, leads to the production of a misfolded protein that aggregates within the endoplasmic reticulum of liver cells, causing liver damage, cirrhosis, and increased risk of hepatocellular carcinoma (Strnad et al., 2020, PubMed: 32534446). Simultaneously, the lack of functional circulating alpha-1 antitrypsin results in uncontrolled protease activity in the lungs, leading to early-onset emphysema. Therapeutic strategies targeting this genomic sequence involve advanced gene editing technologies, such as base editing or CRISPR/Cas9, designed to either correct the mutation or silence the production of the toxic mutant protein (Beam Therapeutics, BEAM-302; Intellia Therapeutics, NTLA-3001). By addressing the disease at the DNA level within the primary site of production, these therapies aim to provide a durable, potentially curative treatment for alpha-1 antitrypsin deficiency. Current clinical efforts focus on using lipid nanoparticles to deliver these editors directly to the hepatocyte nuclei to achieve precise genomic modification.

Other names

PiZ alleleSERPINA1*ZZ-AAT geneAlpha-1 antitrypsin Z mutationGlu342Lys mutation

The mechanism of action involves the precise modification of the SERPINA1 gene at the E342K mutation site using gene editing tools. Base editing (e.g., BEAM-302) converts the mutant lysine codon back to a glutamate or similar functional residue without creating double-strand breaks (Beam Therapeutics). CRISPR/Cas9 or ARCUS-based approaches (e.g., NTLA-3001, PBGENE-AATD) aim to either knock out the mutant allele to stop toxic protein production or insert a functional gene copy to restore systemic protease inhibition (Intellia Therapeutics; Precision BioSciences).