Transvascular delivery of small interfering RNA to the central nervous system

Priti Kumar, Haoquan Wu, Jodi McBride, Kyeong Eun Jung, Moon Hee Kim, Beverly L. Davidson, Sang Kyung Lee, Premlata Shankar, N. Manjunath

Research output: Contribution to journalArticle

817 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)39-43
Number of pages5
JournalNature
Volume448
Issue number7149
DOIs
StatePublished - Jul 7 2007
Externally publishedYes

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Small Interfering RNA
Rabies virus
Central Nervous System
Glycoproteins
Gene Silencing
Blood-Brain Barrier
Peptides
Brain
Viral Encephalitis
Cholinergic Receptors
Therapeutics
Intravenous Injections
Antiviral Agents
Arginine
Anti-Idiotypic Antibodies
Cytokines
Amino Acids

ASJC Scopus subject areas

  • General

Cite this

Kumar, P., Wu, H., McBride, J., Jung, K. E., Hee Kim, M., Davidson, B. L., ... Manjunath, N. (2007). Transvascular delivery of small interfering RNA to the central nervous system. Nature, 448(7149), 39-43. https://doi.org/10.1038/nature05901

Transvascular delivery of small interfering RNA to the central nervous system. / Kumar, Priti; Wu, Haoquan; McBride, Jodi; Jung, Kyeong Eun; Hee Kim, Moon; Davidson, Beverly L.; Kyung Lee, Sang; Shankar, Premlata; Manjunath, N.

In: Nature, Vol. 448, No. 7149, 07.07.2007, p. 39-43.

Research output: Contribution to journalArticle

Kumar, P, Wu, H, McBride, J, Jung, KE, Hee Kim, M, Davidson, BL, Kyung Lee, S, Shankar, P & Manjunath, N 2007, 'Transvascular delivery of small interfering RNA to the central nervous system', Nature, vol. 448, no. 7149, pp. 39-43. https://doi.org/10.1038/nature05901
Kumar P, Wu H, McBride J, Jung KE, Hee Kim M, Davidson BL et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007 Jul 7;448(7149):39-43. https://doi.org/10.1038/nature05901
Kumar, Priti ; Wu, Haoquan ; McBride, Jodi ; Jung, Kyeong Eun ; Hee Kim, Moon ; Davidson, Beverly L. ; Kyung Lee, Sang ; Shankar, Premlata ; Manjunath, N. / Transvascular delivery of small interfering RNA to the central nervous system. In: Nature. 2007 ; Vol. 448, No. 7149. pp. 39-43.
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