N-acetylgalactosamine (GalNAc)-conjugates: Delivering oligonucleotide drugs to the liver

Abstract Oligonucleotide-based therapeutics is a highly promising drug development platform as this can also target candidates which were once considered ‘undruggable’. Despite its promise, specific targeting and delivery of oligonucleotides have been major bottlenecks for its therapeutic utility. Therefore, ongoing efforts are focused on modifications of oligonucleotides to address these limitations. Recent advancements in this area have dramatically enhanced their utility as promising drugs. One such modification is the covalent conjugation of a carbohydrate moiety, N-acetylgalactosamine (GalNAc), to the oligonucleotides. This conjugation of GalNAc facilitates receptor-mediated uptake of oligonucleotides specifically to hepatocytes in the liver. Not only the specific delivery, but GalNAc-oligonucleotide conjugates are also found to be up to 100 folds more potent than its unconjugated counterpart. This approach has shown considerable promise for utilizing oligonucleotides as drugs as it overcomes along-standing problem of oligonucleotide delivery, at least for liver diseases. This development has sparked the quest for conjugates targeting other cell and tissue types.