title: High-density lipoprotein facilitates in vivo delivery of α-tocopherol-conjugated short-interfering RNA to the brain.
abstract: We originally reported the use of vitamin E (α-tocopherol) as an in vivo vector of short-interfering RNA (siRNA) to the liver. Here, we apply our strategy to the brain. By combining high-density lipoprotein (HDL) as a second carrier with α-tocopherol-conjugated siRNA (Toc-siRNA) in the brain, we achieved dramatic improvement of siRNA delivery to neurons. After direct intracerebroventricular (ICV) infusion of Toc-siRNA/HDL for 7 days, extensive and specific knock-down of a target gene, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), was observed in both mRNA and protein levels, especially in the cerebral cortex and hippocampus. This new delivery method achieved a much more prominent down-regulation effect than conventional silencing methods of the brain gene, i.e., ICV infusion of nonconjugated siRNA or oligonucleotides. With only 3 nmol Toc-siRNA with HDL, BACE1 mRNA in the parietal cortex could be reduced by ∼ 70%. We suppose that this dramatic improvement of siRNA delivery to the brain is due to the use of lipoprotein receptor-mediated endocytosis because the silencing efficiency was significantly increased by binding of Toc-siRNA to the lipoprotein, and in contrast, was clearly decreased in lipoprotein-receptor knockout mice. These results suggest exogenous siRNA could be used clinically for otherwise incurable neurological diseases.
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-0034, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Uno
authors.forename: Wenying
authors.initials: W
authors.lastname: Piao
authors.forename: Kanjiro
authors.initials: K
authors.lastname: Miyata
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Nishina
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D001921:Brain / Q000378:metabolism*; D004705:Endocytosis; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D057967:Infusions, Intraventricular; D008075:Lipoproteins, HDL / Q000737:chemistry*; D051379:Mice; D009474:Neurons / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D024502:alpha-Tocopherol / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008075:Lipoproteins, HDL; D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D024502:alpha-Tocopherol