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

  • Author(s): Nair, JK
  • Willoughby, JLS
  • Chan, A
  • Charisse, K
  • Alam, MR
  • Wang, Q
  • Hoekstra, M
  • Kandasamy, P
  • Kelin, AV
  • Milstein, S
  • Taneja, N
  • Oshea, J
  • Shaikh, S
  • Zhang, L
  • Van Der Sluis, RJ
  • Jung, ME
  • Akinc, A
  • Hutabarat, R
  • Kuchimanchi, S
  • Fitzgerald, K
  • Zimmermann, T
  • Van Berkel, TJC
  • Maier, MA
  • Rajeev, KG
  • Manoharan, M
  • et al.

Published Web Location

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

© 2014 American Chemical Society. 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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