Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo**
Muthusamy Jayaraman(Alnylam Pharmaceuticals (United States)), Steven M. Ansell(Encana (Canada)), Barbara L. Mui(Encana (Canada)), Ying K. Tam(Encana (Canada)), Jianxin Chen(Encana (Canada)), Xinyao Du(Encana (Canada)), David Butler(Alnylam Pharmaceuticals (United States)), Laxman Eltepu(Alnylam Pharmaceuticals (United States)), Shigeo Matsuda(Alnylam Pharmaceuticals (United States)), Jayaprakash K. Narayanannair(Alnylam Pharmaceuticals (United States)), Kallanthottathil G. Rajeev(Alnylam Pharmaceuticals (United States)), Ismail M. Hafez(University of British Columbia), Akin Akinc(Alnylam Pharmaceuticals (United States)), Martin A. Maier(Alnylam Pharmaceuticals (United States)), Mark A. Tracy(Alnylam Pharmaceuticals (United States)), Pieter R. Cullis(University of British Columbia), Thomas D. Madden(Encana (Canada)), Muthiah Manoharan(Alnylam Pharmaceuticals (United States)), Michael J. Hope(Encana (Canada))
Cited by 1,217Open Access
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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