Givosiran

Acute hepatic porphyrias are a class of genetic disorders involving deficiencies in the pathway responsible for heme synthesis in liver hepatocytes. The rate-limiting step in heme synthesis is the first enzyme in the pathway, 5-aminolevulinic acid synthase (ALAS1), which is controlled via a negative feedback loop by the presence of heme end-product in the liver. Deficiencies in later enzymes in the pathway result in low circulating levels of heme, which in turn stimulates the up-regulation of ALAS1. The overexpression of ALAS1, in combination with downstream enzyme deficiencies, leads to the overproduction and accumulation of toxic heme intermediates which are ultimately responsible for the neurovisceral symptoms characteristic of acute hepatic porphyrias.

Givosiran is a double-stranded small interfering RNA (siRNA) directed at ALAS1 mRNA in hepatocytes. It is covalently bound to a ligand containing three N-acetylgalactosamine (GalNAc) residues that facilitate uptake into hepatocytes via asialoglycoprotein receptors (ASPGRs), which are highly expressed on the cell surface of hepatocytes and are selective for glycoproteins containing GalNAc residues. Following endocytosis into hepatocytes, the antisense strand of givosiran is loaded into an enzyme complex called the RNA-induced silencing complex (RISC), which uses the antisense strand to seek out and selectively cleave the complementary mRNA sequence (in this case found between nucleotide 918 and 937 of the ALAS1 mRNA). Cleavage of the ALAS1 mRNA results in its degradation, preventing the synthesis of the ALAS1 enzyme and ultimately leading to reduced circulating levels of neurotoxic heme intermediates.