title: Lipid-like materials for low-dose, in vivo gene silencing.
abstract: 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.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Love
authors.forename: Kerry P
authors.initials: KP
authors.lastname: Mahon
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Levins
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Whitehead
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.forename: J Robert
authors.initials: JR
authors.lastname: Dorkin
authors.forename: June
authors.initials: J
authors.lastname: Qin
authors.forename: William
authors.initials: W
authors.lastname: Cantley
authors.forename: Liu Liang
authors.initials: LL
authors.lastname: Qin
authors.forename: Timothy
authors.initials: T
authors.lastname: Racie
authors.forename: Maria
authors.initials: M
authors.lastname: Frank-Kamenetsky
authors.forename: Ka Ning
authors.initials: KN
authors.lastname: Yip
authors.forename: Rene
authors.initials: R
authors.lastname: Alvarez
authors.forename: Dinah W Y
authors.initials: DW
authors.lastname: Sah
authors.forename: Antonin
authors.initials: A
authors.lastname: de Fougerolles
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: 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*
chemical_list: D001672:Biocompatible Materials; D008055:Lipids; D034741:RNA, Small Interfering; D005167:Factor VII