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.
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There have been substantial advances in the small RNA delivery technology into the brain.
“there have been substantial advances in the small RNA delivery technology into the brain.”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Kumar et al., 2007
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- Authors
- Kumar, P., Wu, H., McBride, J. L., Jung, K.-E., Hee Kim, M., Davidson, B. L., Kyung Lee, S., Shankar, P., & Manjunath, N.
- Affiliations
- Harvard University (US)
- University of Iowa (US)
- Samil Pharm (South Korea) (KR)
- Corresponding author
- Shankar, Premlata
- Manjunath, N.
- Venue
- Nature
- Published
- 2007-06-17
- Volume
- 448
- Issue
- 7149
- Pages
- 39-43
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2070693578
- Cited by
- 1,246
- References
- 1
- Citations by year
- 2026: 26 · 2025: 46 · 2024: 52 · 2023: 69 · 2022: 52 · 2021: 66 · 2020: 55 · 2019: 66 · 2018: 49 · 2017: 54 · 2016: 62 · 2015: 76 · 2014: 61 · 2013: 66 · 2012: 86
- FWCI
- 35.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- blood-brain barrier, rabies virus glycoprotein, acetylcholine receptor, viral encephalitis, intravenous delivery, central nervous system therapeutics, arginine-rich peptides
- MeSH terms
- Superoxide Dismutase-1, Amino Acid Sequence, Animals, Blood-Brain Barrier, Brain, Cell Line, Encephalitis Virus, Japanese, Encephalitis, Japanese, Genetic Vectors, Glycoproteins, HeLa Cells, Humans, Liposomes, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Neurons, Oligopeptides, Rabies virus, Receptors, Nicotinic, Recombinant Proteins, Superoxide Dismutase, Viral Proteins, Lentivirus, Drug Delivery Systems, Mice, SCID, Mice, Inbred NOD, Gene Silencing, RNA, Small Interfering, Green Fluorescent Proteins, Mice
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