Acute hepatic porphyrias are monogenic autosomal dominant hereditary disorders involving deficiencies in heme synthesis pathway in liver hepatocytes. 5-aminolevulinic acid synthase (ALAS1) is controlled via a negative feedback loop by heme in the liver. low circulating levels of heme caused by genetic mutation stimulates the up-regulation of #ALAS1. The over-expression of ALAS1, in combination with downstream enzyme deficiencies, leads to the over-production and accumulation of toxic heme intermediates and cause 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. 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 cleave the complementary mRNA to preventing the synthesis of the ALAS1 enzyme and leading to reduced circulating levels of neurotoxic heme intermediates.
Acute hepatic porphyrias are monogenic autosomal dominant hereditary
disorders involving deficiencies in heme synthesis pathway in liver
hepatocytes. 5-aminolevulinic acid synthase (ALAS1) is controlled via a
negative feedback loop by heme in the liver. low circulating levels of heme caused by genetic mutation stimulates the up-regulation of #ALAS1. The over-expression of ALAS1, in combination with downstream enzyme deficiencies,
leads to the over-production and accumulation of toxic heme intermediates
and cause 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. 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 cleave the complementary mRNA to preventing the synthesis of the ALAS1 enzyme and
leading to reduced circulating levels of neurotoxic heme intermediates.