Transvascular delivery of small interfering RNA to the central nervous system

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.

Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects

“…27 The present results represent a major advance in this field given the selective targeting of 5-HT 1A R expressed in 5 vivo. 27,[36][37][38] Hence, the 40% knockdown of 5-HT 1A -autoreceptors produced by singlepoint administration of 30µg C-1A-siRNA is comparable to previous results using prolonged infusion of unmodified siRNA to silence monoamine transporters (400 µgday -1 for 1-2 weeks; 2.8-5.6mg in total, i.e., 90-180-fold the dose used herein). 39,40 Our results agree with previous observations on the detrimental role of 5-HT 1A-autorerceptors in depression.…”

Gene therapy progress and prospects: synthetic polymer-based systems

“…45 Other examples of siRNA polyplexes for receptor-targeted in vivo delivery were recently reported, such as hepatocyte targeting utilizing the asialoglycoprotein receptor, 36 or brain targeting with a rabies virus-derived peptide ligand for the acetyl-choline receptor. 46 Multifunctional polymers can be designed with defined topology and dynamic transport domains…”

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

“…Whether this reagent also targets human DCs and monocytes/macrophages is unclear. We have reported previously that a short 29-aa peptide derived from the rabies virus glycoprotein (RVG), fused to 9R residues (RVG-9R), can deliver siRNA to murine macrophages and brain cells by specific binding to its ligand acetylcholine receptor (AchR) (19,20). Because AchR is also expressed on human macrophages and DCs (21) and also because the acetylcholine-binding site on the α7 subunit is highly conserved, we reasoned that RVG-9R might also be used to target human macrophages and DCs.…”