Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo.
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.
Alnylam Pharmaceuticals, Cambridge, MA, USA. mjayaraman@alnylam.com
Muthusamy
M
Jayaraman
Steven M
SM
Ansell
Barbara L
BL
Mui
Ying K
YK
Tam
Jianxin
J
Chen
Xinyao
X
Du
David
D
Butler
Laxman
L
Eltepu
Shigeo
S
Matsuda
Jayaprakash K
JK
Narayanannair
Kallanthottathil G
KG
Rajeev
Ismail M
IM
Hafez
Akin
A
Akinc
Martin A
MA
Maier
Mark A
MA
Tracy
Pieter R
PR
Cullis
Thomas D
TD
Madden
Muthiah
M
Manoharan
Michael J
MJ
Hope
D000588:Amines / Q000737:chemistry; D000818:Animals; D005260:Female; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007700:Kinetics; D008055:Lipids / Q000008:administration & dosage* / Q000737:chemistry; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics*
D000588:Amines; D008055:Lipids; D008081:Liposomes; D034741:RNA, Small Interfering