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Multivalent N -Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing

2014; American Chemical Society; Volume: 136; Issue: 49 Linguagem: Inglês

10.1021/ja505986a

1943-2984

Jayaprakash K. Nair, Jennifer L. S. Willoughby, Amy Chan, Klaus Charissé, Md. Rowshon Alam, Qianfan Wang, Menno Hoekstra, Kandasamy Pachamuthu, Alexander V. Kel’in, Stuart Milstein, Nate Taneja, Jonathan O′Shea, Sarfraz Shaikh, Ligang Zhang, Ronald J. van der Sluis, Michael E. Jung, Akin Akinc, Renta Hutabarat, Satya Kuchimanchi, Kevin Fitzgerald, Tracy Zimmermann, Theo J.C. van Berkel, Martin A. Maier, Kallanthottathil G. Rajeev, Muthiah Manoharan,

MicroRNA in disease regulation

Conjugation of small interfering RNA (siRNA) to an asialoglycoprotein receptor ligand derived from N-acetylgalactosamine (GalNAc) facilitates targeted delivery of the siRNA to hepatocytes in vitro and in vivo. The ligands derived from GalNAc are compatible with solid-phase oligonucleotide synthesis and deprotection conditions, with synthesis yields comparable to those of standard oligonucleotides. Subcutaneous (SC) administration of siRNA–GalNAc conjugates resulted in robust RNAi-mediated gene silencing in liver. Refinement of the siRNA chemistry achieved a 5-fold improvement in efficacy over the parent design in vivo with a median effective dose (ED50) of 1 mg/kg following a single dose. This enabled the SC administration of siRNA–GalNAc conjugates at therapeutically relevant doses and, importantly, at dose volumes of ≤1 mL. Chronic weekly dosing resulted in sustained dose-dependent gene silencing for over 9 months with no adverse effects in rodents. The optimally chemically modified siRNA–GalNAc conjugates are hepatotropic and long-acting and have the potential to treat a wide range of diseases involving liver-expressed genes.