title: Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo.
abstract: We recently demonstrated that siRNAs conjugated to triantennary N-acetylgalactosamine (GalNAc) induce robust RNAi-mediated gene silencing in the liver, owing to uptake mediated by the asialoglycoprotein receptor (ASGPR). Novel monovalent GalNAc units, based on a non-nucleosidic linker, were developed to yield simplified trivalent GalNAc-conjugated oligonucleotides under solid-phase synthesis conditions. Synthesis of oligonucleotide conjugates using monovalent GalNAc building blocks required fewer synthetic steps compared to the previously optimized triantennary GalNAc construct. The redesigned trivalent GalNAc ligand maintained optimal valency, spatial orientation, and distance between the sugar moieties for proper recognition by ASGPR. siRNA conjugates were synthesized by sequential covalent attachment of the trivalent GalNAc to the 3'-end of the sense strand and resulted in a conjugate with in vitro and in vivo potency similar to that of the parent trivalent GalNAc conjugate design.
authors: Alnylam. Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142 (USA). rajeevk@alnylam.com.
authors: Kallanthottathil G
authors: KG
authors: Rajeev
authors: Jayaprakash K
authors: JK
authors: Nair
authors: Muthusamy
authors: M
authors: Jayaraman
authors: Klaus
authors: K
authors: Charisse
authors: Nate
authors: N
authors: Taneja
authors: Jonathan
authors: J
authors: O'Shea
authors: Jennifer L S
authors: JL
authors: Willoughby
authors: Kristina
authors: K
authors: Yucius
authors: Tuyen
authors: T
authors: Nguyen
authors: Svetlana
authors: S
authors: Shulga-Morskaya
authors: Stuart
authors: S
authors: Milstein
authors: Abigail
authors: A
authors: Liebow
authors: William
authors: W
authors: Querbes
authors: Anna
authors: A
authors: Borodovsky
authors: Kevin
authors: K
authors: Fitzgerald
authors: Martin A
authors: MA
authors: Maier
authors: Muthiah
authors: M
authors: Manoharan
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry*; D000818:Animals; D004337:Drug Carriers / Q000737:chemistry*; D020868:Gene Silencing; D022781:Hepatocytes / Q000378:metabolism*; D051379:Mice; D011228:Prealbumin / Q000172:deficiency / Q000235:genetics; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics*
chemical_list: D004337:Drug Carriers; D011228:Prealbumin; D034741:RNA, Small Interfering; D000116:Acetylgalactosamine
keywords: N-acetylgalactosamine (GalNAc); RNAi; asialoglycoprotein receptor (ASGPR); oligonucleotide conjugates; siRNA