Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of the American Chemical Society, 2014-12, Vol.136 (49), p.16958-16961

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.