Fazirsiran : essais cliniques et état de développement

A formulation composed of the liver-targeted ligand N-acetylgalactosamine (GalNAc) conjugated to small-interfering RNA (siRNA) directed against wild-type and mutant alpha-1 antitrypsin, AAT and Z-AAT, that can potentially be used in the treatment of AAT deficiency (AATD)-associated liver disease. Upon administration of fazirsiran, the GalNAc moiety targets and binds with high affinity to asialoglycoprotein receptors (ASGPRs) expressed on hepatocytes. Once inside the cell, the siRNA binds to and silences AAT and Z-AAT messenger RNA (mRNA) and inhibits both the translation and expression of the AAT and Z-AAT proteins. This decreases the synthesis of the misfolded and poorly secreted Z-AAT protein, which lowers the accumulation of the inflammatory Z-AAT in hepatocytes. This may reduce inflammation and fibrosis, and prevent the progression of liver disease associated with AATD. SERPINA1 gene mutation in AATD leads to AAT deficiency and the production and accumulation of misfolded Z-AAT in the liver, triggering inflammation, fibrosis and hepatocellular injury.