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

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• 作者：Jayaprakash K. Nair ; Jennifer L. S. Willoughby ; Amy Chan ; Klaus Charisse ; Md. Rowshon Alam ; Qianfan Wang ; Menno Hoekstra ; Pachamuthu Kandasamy ; Alexander V. Kel鈥檌n ; Stuart Milstein ; Nate Taneja ; Jonathan O鈥橲hea ; 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
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：December 10, 2014
• 年：2014
• 卷：136
• 期：49
• 页码：16958-16961
• 全文大小：332K
• ISSN：1520-5126

文摘

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鈥揋alNAc 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鈥揋alNAc conjugates at therapeutically relevant doses and, importantly, at dose volumes of 鈮? 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鈥揋alNAc conjugates are hepatotropic and long-acting and have the potential to treat a wide range of diseases involving liver-expressed genes.