title: Enhanced BBB permeability of osmotically active poly(mannitol-co-PEI) modified with rabies virus glycoprotein via selective stimulation of caveolar endocytosis for RNAi therapeutics in Alzheimer's disease.
abstract: RNA interference (RNAi) holds one of the promising tools for Alzheimer's disease (AD) treatment by directly arresting the causative genes. For successful RNAi therapeutics for AD, limited access of therapeutic genes to the brain needs to be overcome by developing siRNA delivery system that could cross the blood-brain barrier (BBB). Here, we report a non-viral vector, rabies virus glycoprotein (RVG)-modified poly(mannitol-co-PEI) gene transporter (PMT), R-PEG-PMT. The RVG ligand directed the PMT/siRNA complexes toward the brain through binding to nicotinic acetylcholine receptors expressed on BBB. In mechanistic study using in vitro BBB model, we observed that osmotically-active PMT enhanced the receptor-mediated transcytosis by stimulating the caveolar endocytosis. The potential of RNAi therapeutics for AD using R-PEG-PMT/siBACE1 complexes was demonstrated in vitro and in vivo. Our results suggest that R-PEG-PMT is a powerful gene carrier system for brain targeted RNAi therapeutics with synergistic effect of RVG ligand and PMT on well-modulated receptor-mediated transcytosis through BBB.
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Tae-Eun
authors.initials: TE
authors.lastname: Park
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Bijay
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Huishan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea.
authors.forename: Jun-Yeong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Institute of Green-Bio Science & Technology, Seoul National University, Pyeongchanggun, Gangwondo 232-916, South Korea.
authors.forename: Sang-Kee
authors.initials: SK
authors.lastname: Kang
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea. Electronic address: cyjcow@snu.ac.kr.
authors.forename: Yun-Jaie
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Agricultural Biotechnology & Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, South Korea. Electronic address: chocs@snu.ac.kr.
authors.forename: Chong-Su
authors.initials: CS
authors.lastname: Cho
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000628:therapy; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D021941:Caveolae / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods; D006023:Glycoproteins / Q000737:chemistry / Q000493:pharmacokinetics*; D008353:Mannitol / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009997:Osmotic Pressure; D010539:Permeability; D011094:Polyethyleneimine / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D011820:Rabies virus / Q000737:chemistry*; D014018:Tissue Distribution; D014764:Viral Proteins / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D006023:Glycoproteins; D034741:RNA, Small Interfering; D014764:Viral Proteins; D008353:Mannitol; D011094:Polyethyleneimine
keywords: Alzheimer's disease; Blood–brain barrier; Caveolae-mediated endocytosis; Mannitol; Polyethylenimine; RNA interference