ALN-F12 for HAE prophylaxis: therapeutic hypothesis. (A) ALN-F12 silences hepatic F12 gene expression. N-acetylgalactosamine (GalNAc) conjugated siRNA duplex ALN-F12 specifically binds hepatocytes via the asialoglycoprotein receptor (ASGPR). Following calthrin-mediated endocytosis and endosomal escape, ALN-F12 is unwound and loaded into RISC (RNA-induced silencing complex) and specifically recognizes and degrades F12 mRNA, leading to a reduction of secreted Factor XII (FXII) protein levels in plasma. (B) Conversion of FXII to FXIIa initiates an enzymatic signaling cascade that results in the production of bradykinin, a peptide signal that controls vascular permeability. C1 esterase inhibitor (C1INH), which binds and inhibits FXIIa and plasma kallikrein (PKa), negatively regulates this process. In HAE patients, loss of C1INH activity leads to excess bradykinin generation, resulting in increased vascular permeability and subsequent edema. RNAi-mediated knockdown of F12 gene expression by ALN-F12 would decrease circulating FXII protein levels and therefore preventing excess bradykinin generation.
