Lipid-like materials for low-dose, in vivo gene silencing.
Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system.
Love
Kevin T
KT
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Mahon
Kerry P
KP
Levins
Christopher G
CG
Whitehead
Kathryn A
KA
Querbes
William
W
Dorkin
J Robert
JR
Qin
June
J
Cantley
William
W
Qin
Liu Liang
LL
Racie
Timothy
T
Frank-Kamenetsky
Maria
M
Yip
Ka Ning
KN
Alvarez
Rene
R
Sah
Dinah W Y
DW
de Fougerolles
Antonin
A
Fitzgerald
Kevin
K
Koteliansky
Victor
V
Akinc
Akin
A
Langer
Robert
R
Anderson
Daniel G
DG
D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis / Q000737:chemistry*; D016503:Drug Delivery Systems; D005167:Factor VII / Q000037:antagonists & inhibitors / Q000235:genetics; D020868:Gene Silencing; D006367:HeLa Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000138:chemical synthesis / Q000737:chemistry*; D008252:Macaca fascicularis; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*
D001672:Biocompatible Materials; D008055:Lipids; D034741:RNA, Small Interfering; D005167:Factor VII