Transvascular delivery of small interfering RNA to the central nervous system

Priti Kumar, Haoquan Wu, Jodi L. McBride, Kyeong-Eun Jung, Moon Hee Kim, Beverly L. Davidson, Sang Kyung Lee, Premlata Shankar () and N. Manjunath ()
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Priti Kumar: Harvard Medical School, Boston, Massachusetts 02115, USA
Haoquan Wu: Harvard Medical School, Boston, Massachusetts 02115, USA
Jodi L. McBride: Roy J. and Lucille J. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
Kyeong-Eun Jung: Research Center, Samchully Pharm. Co. Ltd., Seoul 135-735, Korea
Moon Hee Kim: Research Center, Samchully Pharm. Co. Ltd., Seoul 135-735, Korea
Beverly L. Davidson: Roy J. and Lucille J. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
Sang Kyung Lee: Hanyang University, Seoul 133-791, Korea
Premlata Shankar: Harvard Medical School, Boston, Massachusetts 02115, USA
N. Manjunath: Harvard Medical School, Boston, Massachusetts 02115, USA

Nature, 2007, vol. 448, issue 7149, 39-43

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05901

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