Nature：siRNA能帮助药物穿过血脑屏障到达大脑
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（Japanese encephalitis virus ，JEV）感染。
实验过程中，哈佛医学院血液研究所Manjunath N. 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
Transvascular delivery of small interfering RNA to the central nervous system
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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