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JK Nair, JL Willoughby, A Chan, K Charisse, MR Alam, Q Wang, M Hoekstra, P Kandasamy, AV Kel'in, S Milstein, N Taneja, J O'Shea, S Shaikh, L Zhang, RJ van der Sluis, ME Jung, A Akinc, R Hutabarat, S Kuchimanchi, K Fitzgerald, T Zimmermann, TJ van Berkel, MA Maier, KG Rajeev and M Manoharan
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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Dose, Oligonucleotide synthesis, Small interfering RNA, Molecular biology, Gene silencing, RNA interference, Gene expression, RNA
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