生物谷报道：血脑屏障（blood-brain）阻止治疗性药物到达大脑，因此是治疗脑部感染或其它脑部疾病的一大障碍。研究人员最近发现，通过静脉注射，一种来自于狂犬病毒的肽能够将治疗性小干扰RNA（siRNA）携带到大脑，到达脑神经细胞后，siRNA能够帮助小鼠抵抗日本脑炎病毒（Japaneseencephalitisvirus，JEV）感染。

实验过程中，哈佛医学院血液研究所ManjunathN.Swamy博士与其同事使小鼠脑部感染JEV，然后向部分小鼠尾部静脉注射与狂犬病毒肽绑定在一起的siRNA，剩下的小鼠作为对照组。结果，所有对照组小鼠死于JEV感染，获得抗病毒siRNA的实验组小鼠80％存活下来。这些说明狂犬病毒肽能够递送抗病毒siRNA穿过血脑屏障到达脑神经细胞，到达后抗病毒siRNA沉默关键的病毒基因进而控制感染。而且，多次RNAi治疗不会激发免疫反应和产生肽的抗体。

目前，医生使用各种方法将治疗药物直接递送到大脑，比如入侵性的围绕感染位点的局部递送。新方法提供了一个安全而无入侵性的方法，使治疗性分子穿过血脑屏障，有望治疗各种脑部感染。研究人员目前正试图改善这种递送系统的效果，摸索一种稳定高效的siRNA形式。

原始出处:

Nature advance online publication 17 June 2007 | doi:10.1038/nature05901; Received 4 January 2007; Accepted 2 May 2007; Published online 17 June 2007

Priti Kumar1, Haoquan Wu1, Jodi L. McBride2, Kyeong-Eun Jung3, Moon Hee Kim3, Beverly L. Davidson2, Sang Kyung Lee4, Premlata Shankar1 N. Manjunath1 The CBR Institute for Biomedical Research and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA Department of Internal Medicine, Roy J. and Lucille J. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA Research Center, Samchully Pharm. Co. Ltd., Seoul 135-735, Korea 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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