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

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

来源：Journal of the American Chemical Society, 2014, 136(49): 16958-16961.

DOI：10.1021/ja505986a

• SOLID-PHASE SYNTHESIS
• IN-VIVO DELIVERY
• ASIALOGLYCOPROTEIN RECEPTOR
• THERAPEUTICS
• NANOPARTICLES
• PROTEINS
• LIGANDS

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.

• 出版日期2014-12-20