title: Lipophilic siRNAs mediate efficient gene silencing in oligodendrocytes with direct CNS delivery.
abstract: Conjugation of small interfering RNA (siRNA) with lipophilic molecules has been demonstrated to enhance cellular uptake in cell culture and to produce efficient endogenous gene silencing in the liver after systemic administration and in neurons after direct local injection. Here, we evaluated the in vivo delivery of siRNAs conjugated with different linkers to cholesterol by targeting CNPase (2'-3'-cyclic nucleotide 3'-phosphodiesterase) in oligodendrocytes. Cholesterol-conjugated siRNAs administered to the rat corpus callosum by intraparenchymal central nervous system (CNS) infusion show improved silencing ability compared with unconjugated siRNA. Furthermore, conjugation of siRNA to cholesterol with a cleavable disulfide linker appears to be beneficial for improving the potency of silencing of CNPase mRNA in oligodendrocytes in vivo. Taken together, these findings indicate that cholesterol-conjugated siRNAs are effective for direct CNS delivery to oligodendrocytes, and that the biocleavable disulfide linker appears to be beneficial for improving the potency of silencing of target mRNA in vivo.
authors.affiliation: Alnylam Pharmaceuticals Inc., 300 Third Street, Cambridge, MA 02142, USA. qchen@alnylam.com
authors.forename: Qingmin
authors.initials: Q
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Butler
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Pandey
authors.forename: Pei
authors.initials: P
authors.lastname: Ge
authors.forename: Martin A
authors.initials: MA
authors.lastname: Maier
authors.forename: Ligang
authors.initials: L
authors.lastname: Zhang
authors.forename: Kallanthottathil G
authors.initials: KG
authors.lastname: Rajeev
authors.forename: Lubomir
authors.initials: L
authors.lastname: Nechev
authors.forename: Victor
authors.initials: V
authors.lastname: Kotelianski
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Dinah W Y
authors.initials: DW
authors.lastname: Sah
mesh_terms: D000818:Animals; D002490:Central Nervous System; D002784:Cholesterol / Q000235:genetics; D020868:Gene Silencing; D008297:Male; D009474:Neurons; D009836:Oligodendroglia; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D002784:Cholesterol