Figure 2.

A detailed overview of GalNAc–siRNA mechanism of action in the hepatocyte. A GalNAc–siRNA drug is administered subcutaneously and the GalNAc moiety binds the ASGPR on the hepatocyte cell membrane. The drug conjugate enters the cell via an endosomal mechanism, following which it escapes into the cytosol and the ASGPR recycles to the cell surface. The siRNA sense and antisense strands dissociate, and the antisense strand binds its target sequence in the LPA gene mRNA. Binding of the antisense strand induces degradation of LPA mRNA, preventing its translation into apo(a) and thereby reducing the synthesis of Lp(a). GalNAc, N-acetyl-galactosamine; ASGPR, asialoglycoprotein receptor; RISC, RNA-induced silencing complex; RNAi, RNA interference; AAA, gene transcript.