GalNAc, or N-acetylgalactosamine, is a sugar molecule with its chemical structure shown in Figure 1. It can recognize and bind to a cell surface protein, the asialoglycoprotein receptor (ASGPR), which is abundantly expressed on mammalian liver cells (hepatocytes). GalNAc is then taken up by the cell through endosomes. The ASGPR is also expressed in several human carcinoma cell lines, as well as in the glandular cells of the gallbladder and the stomach.
GalNAc has been used for selectively targeting liver cells, either by conjugating it through a linker with a drug substance or by using a delivery platform like lipid nanoparticles (LNPs). Alnylam has a couple of FDA-approved siRNA products that conjugate siRNA molecules with the GalNAc sugar molecule to increase the stability and selectivity of the drug products, such as givosiran for the treatment of acute hepatic porphyria, lumasiran for the treatment of primary hyperoxaluria type 1, etc. GalNAc can also be incorporated into lipid nanoparticles that encapsulate the drug substance. For example, the recent positive base editing early Phase I trial from Verve Therapeutics used an LNP-GalNAc delivery system to deliver modified CRISPR-Cas9 and lower blood LDL-C levels in people with homozygous familial hypercholesterolemia (HoFH).
GalNAc has garnered significant attention for targeted therapies. The advantages of using GalNAc as the targeting ligand include high liver specificity, enhanced cellular uptake, reduced dosing requirements, minimized systemic distribution, minimal immunogenicity, and a history of past clinical success.