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Six therapeutics that use N-acetylgalactosamine (GalNAc) as a targeting ligand for hepatocytes have been approved so far. All of them are oligonucleotide therapeutics, with five being small interfering RNAs (siRNAs) and one being an antisense oligonucleotide (ASO). Many GalNAc-modified compounds are lined up in the pipelines of manufacturers developing these classes of therapeutics, and the number of GalNAc-modified therapeutics is expected to increase in the future. The term ESC in the item name is an abbreviation for “enhanced stabilized chemistry,” which refers to a technology developed by Alnylam Pharmaceuticals (hereinafter referred to as Alnylam) that maintains high metabolic stability [1]. Specifically, it is a stabilized modified nucleic acid that combines 2′-O-methyl RNA and 2′-fluoro RNA modified with a sugar part, in addition to a phosphorothioate modification in which one of the oxygen atoms of the phosphate diester bond is replaced with a sulfur atom. Inclisiran (Fig. 123.1), a hypercholesterolemia drug developed with ESC-GalNAc technology, has extremely high metabolic stability, enabling administration once every 6 months [2]. In Alnylam’s ESC-GalNAc, a three-branched sugar chain with a terminal GalNAc residue is used. This is because the asialoglycoprotein receptor (ASGPR), which recognizes GalNAc, is composed of three subunits, each with one sugar recognition domain, and the “cluster effect” is observed, where the binding affinity dramatically increases as the number of GalNAc increases from one to three [3]. Dicerna Pharmaceuticals has developed GalXC technology, where four monomeric GalNAc-modified RNA units are connected in a row, and has launched one siRNA drug (nedosiran) [4]. On the other hand, one ASO (eplontersen) has been launched by Ionis Pharmaceuticals (hereinafter referred to as Ionis). Ionis has developed ligand-conjugated antisense (LICA) technology, and in addition to the three-branched GalNAc used in eplontersen, the use of glucagon-like peptide-1 receptor ligands is being considered [5].

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Drug Discovery Using ESC-GalNAc

  • 章节

  • 发表日期：

    2026年

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  • Makiya Nishikawa

摘要

Six therapeutics that use N-acetylgalactosamine (GalNAc) as a targeting ligand for hepatocytes have been approved so far. All of them are oligonucleotide therapeutics, with five being small interfering RNAs (siRNAs) and one being an antisense oligonucleotide (ASO). Many GalNAc-modified compounds are lined up in the pipelines of manufacturers developing these classes of therapeutics, and the number of GalNAc-modified therapeutics is expected to increase in the future. The term ESC in the item name is an abbreviation for “enhanced stabilized chemistry,” which refers to a technology developed by Alnylam Pharmaceuticals (hereinafter referred to as Alnylam) that maintains high metabolic stability [1]. Specifically, it is a stabilized modified nucleic acid that combines 2′-O-methyl RNA and 2′-fluoro RNA modified with a sugar part, in addition to a phosphorothioate modification in which one of the oxygen atoms of the phosphate diester bond is replaced with a sulfur atom. Inclisiran (Fig. 123.1), a hypercholesterolemia drug developed with ESC-GalNAc technology, has extremely high metabolic stability, enabling administration once every 6 months [2]. In Alnylam’s ESC-GalNAc, a three-branched sugar chain with a terminal GalNAc residue is used. This is because the asialoglycoprotein receptor (ASGPR), which recognizes GalNAc, is composed of three subunits, each with one sugar recognition domain, and the “cluster effect” is observed, where the binding affinity dramatically increases as the number of GalNAc increases from one to three [3]. Dicerna Pharmaceuticals has developed GalXC technology, where four monomeric GalNAc-modified RNA units are connected in a row, and has launched one siRNA drug (nedosiran) [4]. On the other hand, one ASO (eplontersen) has been launched by Ionis Pharmaceuticals (hereinafter referred to as Ionis). Ionis has developed ligand-conjugated antisense (LICA) technology, and in addition to the three-branched GalNAc used in eplontersen, the use of glucagon-like peptide-1 receptor ligands is being considered [5].