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

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

Authors :
Nair, Jayaprakash K
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
Nair, Jayaprakash K
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
Source :
Journal of the American Chemical Society; vol 136, iss 49, 16958-16961; 0002-7863
Publication Year :
2014

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.

Details

Database :
OAIster
Journal :
Journal of the American Chemical Society; vol 136, iss 49, 16958-16961; 0002-7863
Notes :
application/pdf, Journal of the American Chemical Society vol 136, iss 49, 16958-16961 0002-7863
Publication Type :
Electronic Resource
Accession number :
edsoai.on1287430839
Document Type :
Electronic Resource