title: Direct CNS delivery of siRNA mediates robust silencing in oligodendrocytes.
abstract: The most significant challenge remaining in the development of small interfering RNAs (siRNAs) as a new class of therapeutic drugs is successful delivery in vivo. The majority of reported studies describing delivery of siRNA or short hairpin RNA (shRNA) to the central nervous system (CNS) have focused on RNA interference (RNAi) in neurons. Here we show direct CNS delivery of siRNA to a different cell type-oligodendrocytes-using convection-enhanced delivery, and demonstrate robust silencing of an endogenous oligodendrocyte-specific gene, 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) with siRNA formulated in saline. The silencing is not sequence-dependent as several different siRNAs are effective in inhibiting target gene expression. Furthermore, we show that CNPase mRNA reduction is dose-dependent, durable for up to 1 week, and mediated by an RNAi mechanism. Increasing the flow rate of siRNA infusion increased the distribution of mRNA suppression to encompass white matter regions distant from the infusion site. Finally, we demonstrate suppression of CNPase mRNA in the nonhuman primate CNS. Taken together, these results show for the first time robust RNAi within oligodendrocytes in vivo and demonstrate the important potential of siRNAs in the treatment of CNS disorders involving oligodendrocyte pathology.
authors.affiliation: Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts 02142, USA. wquerbes@alnylam.com
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.forename: Pei
authors.initials: P
authors.lastname: Ge
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Fan
authors.forename: Jason
authors.initials: J
authors.lastname: Costigan
authors.forename: Klaus
authors.initials: K
authors.lastname: Charisse
authors.forename: Martin
authors.initials: M
authors.lastname: Maier
authors.forename: Lubomir
authors.initials: L
authors.lastname: Nechev
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Victor
authors.initials: V
authors.lastname: Kotelianski
authors.forename: Dinah W Y
authors.initials: DW
authors.lastname: Sah
mesh_terms: D000818:Animals; D001483:Base Sequence; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D034741:RNA, Small Interfering