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Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing.

  • Author(s): Nair, Jayaprakash K
  • Willoughby, Jennifer LS
  • 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 JC
  • Maier, Martin A
  • Rajeev, Kallanthottathil G
  • Manoharan, Muthiah
  • et al.

Published Web Location

https://doi.org/10.1021/ja505986a
Abstract

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.

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