Transvascular delivery of small interfering RNA to the central nervous system

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. Since the discovery of gene silencing by naturally occurring small interfering RNA (siRNA) molecules, the idea that they might be used therapeutically has been up and running. Several reports of systemic delivery of siRNAs have been published, but the brain was not among the targets, because of that old problem, the blood–brain barrier. Now a collaboration between labs in the United States and South Korea has developed a way of delivering siRNAs across the barrier. The method, which is suitable for other types of drug as well as siRNA, makes use of a short peptide derived from the rabies virus as a transporter for the RNA. As well as delivering the RNA into neuronal cells in cell culture, an antiviral siRNA was delivered specifically into the brains of mice infected with encephalitis: about 80% of the mice survived the normally fatal infection. If replicated in humans, this work could lead to the development of noninvasive intravenous treatments for neurological disorders. Attachment of a piece of viral protein to a small RNA achieves transfer of the RNA into neuronal cells in cell culture. This was also able to deliver an antiviral siRNA specifically into the brains of mice infected with encephalitis and achieve 80% protection. This study opens a new potential line of treatment for neuronal disease.