吉伏司瑞 (Givlaari)

概览

Givosiran is a 5-aminolevulinic acid synthase-directed small interfering RNA (siRNA) used in the prophylaxis of acute hepatic porphyria.

作用机制

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.

适应症

用于治疗急性肝卟啉症（AHP）。 AHP是一类非常罕见的遗传性疾病（罕见病），其特征是使人衰弱的、潜在危及生命的发作，对一些患者来说，疾病的慢性表现会对日常功能和生活质量产生负面影响。AHP的长期并发症包括慢性神经性疼痛、高血压、慢性肾病和肝病。

• Acute Hepatic Porphyria (AHP)