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Transvascular delivery of small interfering RNA to the central nervous system
Kumar, Priti,Wu, Haoquan,McBride, Jodi L.,Jung, Kyeong-Eun,Hee Kim, Moon,Davidson, Beverly L.,Kyung Lee, Sang,Shankar, Premlata,Manjunath, N. Nature Publishing Group 2007 Nature Vol.448 No.7149
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.
RNAi-mediated CCR5 Silencing by LFA-1-targeted Nanoparticles Prevents HIV Infection in BLT Mice
Kim, Sang-Soo,Peer, Dan,Kumar, Priti,Subramanya, Sandesh,Wu, Huaquan,Asthana, Deshratan,Habiro, Katsuyoshi,Yang, Yong-Guang,Manjunath, N,Shimaoka, Motomu,Shankar, Premlata Elsevier 2010 Molecular therapy Vol.18 No.2