nonaarginine and Encephalitis--Japanese

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.

Topics: Amino Acid Sequence; Animals; Blood-Brain Barrier; Brain; Cell Line; Drug Delivery Systems; Encephalitis Virus, Japanese; Encephalitis, Japanese; Gene Silencing; Genetic Vectors; Glycoproteins; Green Fluorescent Proteins; HeLa Cells; Humans; Lentivirus; Liposomes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Molecular Sequence Data; Neurons; Oligopeptides; Rabies virus; Receptors, Nicotinic; Recombinant Proteins; RNA, Small Interfering; Superoxide Dismutase; Superoxide Dismutase-1; Viral Proteins