Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo**

Jayaraman, Muthusamy; Ansell, Steven M.; Mui, Barbara L.; Tam, Ying K.; Chen, Jianxin; Du, Xinyao; Butler, David; Eltepu, Laxman; Matsuda, Shigeo; Narayanannair, Jayaprakash K.; Rajeev, Kallanthottathil G.; Hafez, Ismail M.; Akinc, Akin; Maier, Martin A.; Tracy, Mark A.; Cullis, Pieter R.; Madden, Thomas D.; Manoharan, Muthiah; Hope, Michael J.

doi:10.1002/anie.201203263

articleAngewandte Chemie International EditionJul 10, 2012BRONZE OA

Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo**

MJMuthusamy Jayaraman SMSteven M. Ansell BLBarbara L. Mui YKYing K. Tam JCJianxin Chen

Alnylam Pharmaceuticals (United States) · Encana (Canada) · +1 more institution

PubMed

Indexed incrossrefpubmed

Abstract

Special (lipid) delivery: The role of the ionizable lipid pK(a) in the in vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pK(a) value and silencing of the mouse FVII gene (FVII ED(50) ) was found, with an optimal pK(a) range of 6.2-6.5. The most potent cationic lipid from this study has ED(50) levels around 0.005 mg kg(-1) in mice and less than 0.03 mg kg(-1) in non-human primates.

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Topics & keywords

Topics

Keywords

Gene silencing
In vivo
Potency
Chemistry
In vitro
Gene delivery
Lipid metabolism
Cationic polymerization

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Funding

CI
Canadian Institutes of Health Research