title: Transvascular delivery of small interfering RNA to the central nervous system.
abstract: A major impediment in the treatment of neurological diseases is the presence of the blood-brain barrier, which precludes the entry of therapeutic molecules from blood to brain. Here we show that a short peptide derived from rabies virus glycoprotein (RVG) enables the transvascular delivery of small interfering RNA (siRNA) to the brain. This 29-amino-acid peptide specifically binds to the acetylcholine receptor expressed by neuronal cells. To enable siRNA binding, a chimaeric peptide was synthesized by adding nonamer arginine residues at the carboxy terminus of RVG. This RVG-9R peptide was able to bind and transduce siRNA to neuronal cells in vitro, resulting in efficient gene silencing. After intravenous injection into mice, RVG-9R delivered siRNA to the neuronal cells, resulting in specific gene silencing within the brain. Furthermore, intravenous treatment with RVG-9R-bound antiviral siRNA afforded robust protection against fatal viral encephalitis in mice. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or anti-peptide antibodies. Thus, RVG-9R provides a safe and noninvasive approach for the delivery of siRNA and potentially other therapeutic molecules across the blood-brain barrier.
authors.affiliation: The CBR Institute for Biomedical Research and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Priti
authors.initials: P
authors.lastname: Kumar
authors.forename: Haoquan
authors.initials: H
authors.lastname: Wu
authors.forename: Jodi L
authors.initials: JL
authors.lastname: McBride
authors.forename: Kyeong-Eun
authors.initials: KE
authors.lastname: Jung
authors.forename: Moon Hee
authors.initials: MH
authors.lastname: Kim
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
authors.forename: Sang Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Premlata
authors.initials: P
authors.lastname: Shankar
authors.forename: N
authors.initials: N
authors.lastname: Manjunath
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D016503:Drug Delivery Systems; D004664:Encephalitis Virus, Japanese; D004672:Encephalitis, Japanese / Q000517:prevention & control; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics; D006023:Glycoproteins / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism / Q000821:virology; D009842:Oligopeptides / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D011820:Rabies virus / Q000235:genetics / Q000502:physiology; D011978:Receptors, Nicotinic / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014764:Viral Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D008081:Liposomes; D009842:Oligopeptides; D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; C000606290:SOD1 protein, human; D014764:Viral Proteins; C491427:nonaarginine; D049452:Green Fluorescent Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1