title: Efficient in vivo delivery of siRNA to the liver by conjugation of alpha-tocopherol.
abstract: RNA interference is a powerful tool for target-specific knockdown of gene expression. However, efficient and safe in vivo delivery of short interfering RNA (siRNA) to the target organ, which is essential for therapeutic applications, has not been established. In this study we used alpha-tocopherol (vitamin E), which has its own physiological transport pathway to most of the organs, as a carrier molecule of siRNA in vivo. The alpha-tocopherol was covalently bound to the antisense strand of 27/29-mer siRNA at the 5'-end (Toc-siRNA). The 27/29-mer Toc-siRNA was designed to be cleaved by Dicer, producing a mature form of 21/21-mer siRNA after releasing alpha-tocopherol. The C6 hydroxyl group of alpha-tocopherol, associated with antioxidant activity, was abolished. Using this new vector, intravenous injection of 2 mg/kg of Toc-siRNA, targeting apolipoprotein B (apoB), achieved efficient reduction of endogenous apoB messenger RNA (mRNA) in the liver. The downregulation of apoB mRNA was confirmed by the accumulation of lipid droplets in the liver as a phenotype. Neither induction of interferons (IFNs) nor other overt side effects were revealed by biochemical and pathological analyses. These findings indicate that Toc-siRNA is effective and safe for RNA interference-mediated gene silencing in vivo.
authors: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors: Kazutaka
authors: K
authors: Nishina
authors: Toshinori
authors: T
authors: Unno
authors: Yoshitaka
authors: Y
authors: Uno
authors: Takayuki
authors: T
authors: Kubodera
authors: Tadashi
authors: T
authors: Kanouchi
authors: Hidehiro
authors: H
authors: Mizusawa
authors: Takanori
authors: T
authors: Yokota
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004337:Drug Carriers; D020868:Gene Silencing; D007372:Interferons / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D024502:alpha-Tocopherol
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D004337:Drug Carriers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D007372:Interferons; D024502:alpha-Tocopherol