Serpin family A member 1 PiZ-variant messenger RNA (SERPINA1 PiZ mRNA) (SERPINA1 PiZ mRNA)

SERPINA1 PiZ-variant mRNA is the messenger RNA transcript derived from the mutated SERPINA1 gene, specifically carrying the Z mutation (Glu342Lys) (Strnad et al., 2020, NEJM). This mutation leads to the production of misfolded alpha-1 antitrypsin (AAT) protein that polymerizes and becomes trapped within the endoplasmic reticulum of hepatocytes, causing proteotoxicity and chronic liver disease (Turner et al., 2023, NEJM). As a therapeutic target, this mRNA is addressed using RNA interference (RNAi) or antisense oligonucleotides (ASOs) to silence the expression of the toxic Z-AAT protein (Alnylam Pharmaceuticals, 2024). Drugs like Fazirsiran and Belcesiran utilize this mechanism to reduce the hepatic burden of protein aggregates, aiming to halt or reverse liver fibrosis (Arrowhead Pharmaceuticals, 2023). While effective for liver manifestations, this approach does not address the pulmonary deficiency of AAT, as it further reduces the already low levels of circulating protein, potentially exacerbating lung disease (Teckman et al., 2020, Orphanet Journal of Rare Diseases). Consequently, monitoring of lung function is often required during treatment with these RNA-targeting therapies (PubMed, 2023).

Other names

Alpha-1 antitrypsin Z-variant mRNAAAT-Z mRNAZ-AAT mRNASERPINA1*Z mRNAAlpha-1 antitrypsin PiZ mRNA

RNA interference (RNAi) or antisense-mediated degradation of the mRNA transcript to prevent the translation and subsequent accumulation of misfolded Alpha-1 antitrypsin protein in hepatocytes (Turner et al., 2023, NEJM).