1. The CBR Institute for Biomedical Research and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Department of Internal Medicine, Roy J. and Lucille J. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
3. Research Center, Samchully Pharm. Co. Ltd., Seoul 135-735, Korea
4. Department of Bioengineering and Hanyang Fusion Materials Program, Hanyang University, Seoul 133-791, Korea

Correspondence to: Premlata Shankar¹N. Manjunath¹ Correspondence and requests for materials should be addressed to Email: N.M. (swamy@cbrinstitute.org) or P.S. (Email: shankar@cbrinstitute.org).

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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