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, N. Manjunath

    Research output: Contribution to journalArticlepeer-review

    873 Scopus citations

    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

    ASJC Scopus subject areas

    • General

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