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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Blood-Brain Barrier
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Brain* / metabolism
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Brain* / virology
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Cell Line
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Drug Delivery Systems*
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Encephalitis Virus, Japanese
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Encephalitis, Japanese / prevention & control
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Gene Silencing
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Genetic Vectors / genetics
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Glycoproteins / administration & dosage*
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Glycoproteins / genetics
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Glycoproteins / metabolism
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Green Fluorescent Proteins / genetics
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HeLa Cells
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Humans
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Lentivirus / genetics
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Liposomes
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, SCID
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Molecular Sequence Data
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Neurons / metabolism
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Neurons / virology
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Oligopeptides / genetics
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RNA, Small Interfering / administration & dosage*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rabies virus / genetics
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Rabies virus / physiology
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Receptors, Nicotinic / metabolism
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Superoxide Dismutase / genetics
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Superoxide Dismutase-1
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Viral Proteins / administration & dosage
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Viral Proteins / genetics
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Viral Proteins / metabolism
Substances
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Glycoproteins
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Liposomes
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Oligopeptides
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RNA, Small Interfering
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Receptors, Nicotinic
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Recombinant Proteins
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SOD1 protein, human
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Viral Proteins
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nonaarginine
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Green Fluorescent Proteins
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1