Alpha-1 antitrypsin PiZ-mutant messenger RNA (SERPINA1 PiZ mRNA) (SERPINA1 PiZ mRNA)

SERPINA1 PiZ-mutant mRNA is the messenger RNA transcript of the SERPINA1 gene containing the PiZ mutation (Glu342Lys), which is the primary cause of severe Alpha-1 antitrypsin deficiency (AATD). This specific mutation leads to the synthesis of a misfolded alpha-1 antitrypsin (AAT) protein that polymerizes and accumulates within the endoplasmic reticulum of hepatocytes (UniProt P01009). The resulting intrahepatic accumulation causes a toxic gain-of-function, leading to chronic liver inflammation, fibrosis, and an increased risk of cirrhosis or hepatocellular carcinoma (NIH GARD). As a therapeutic target, this mRNA is addressed using gene-silencing technologies such as RNA interference (RNAi) and antisense oligonucleotides (ASOs) to prevent the translation of the toxic protein. By reducing the production of mutant Z-AAT at the source, these therapies aim to decrease the hepatic protein burden and allow for liver recovery and regeneration (Strnad et al., NEJM 2022). This approach specifically targets the liver manifestations of AATD, distinct from augmentation therapies that address the lung-related loss-of-function. Clinical candidates like fazirsiran have demonstrated the ability to significantly lower Z-AAT levels and improve histological markers of liver health in phase 2 trials.

Other names

SERPINA1 Z-variant mRNAAAT-PiZ mRNAAlpha-1 antitrypsin Z-mutation transcriptZ-AAT mRNA

RNA interference (RNAi) or antisense-mediated degradation leading to gene silencing and reduction of mutant protein synthesis.