生物谷報(bào)道：血腦屏障（blood-brain ）阻止治療性藥物到達(dá)大腦,，因此是治療腦部感染或其它腦部疾病的一大障礙,。研究人員最近發(fā)現(xiàn)，通過(guò)靜脈注射，一種來(lái)自于狂犬病毒的肽能夠?qū)⒅委熜孕「蓴_RNA（siRNA）攜帶到大腦,，到達(dá)腦神經(jīng)細(xì)胞后,，siRNA能夠幫助小鼠抵抗日本腦炎病毒（Japanese encephalitis virus ,，JEV）感染,。
實(shí)驗(yàn)過(guò)程中，哈佛醫(yī)學(xué)院血液研究所Manjunath N. Swamy博士與其同事使小鼠腦部感染JEV,，然后向部分小鼠尾部靜脈注射與狂犬病毒肽綁定在一起的siRNA,，剩下的小鼠作為對(duì)照組。結(jié)果,，所有對(duì)照組小鼠死于JEV感染,，獲得抗病毒siRNA的實(shí)驗(yàn)組小鼠80％存活下來(lái),。這些說(shuō)明狂犬病毒肽能夠遞送抗病毒siRNA穿過(guò)血腦屏障到達(dá)腦神經(jīng)細(xì)胞,，到達(dá)后抗病毒siRNA沉默關(guān)鍵的病毒基因進(jìn)而控制感染。而且,，多次RNAi治療不會(huì)激發(fā)免疫反應(yīng)和產(chǎn)生肽的抗體,。
目前，醫(yī)生使用各種方法將治療藥物直接遞送到大腦,，比如入侵性的圍繞感染位點(diǎn)的局部遞送,。新方法提供了一個(gè)安全而無(wú)入侵性的方法，使治療性分子穿過(guò)血腦屏障,，有望治療各種腦部感染,。研究人員目前正試圖改善這種遞送系統(tǒng)的效果，摸索一種穩(wěn)定高效的siRNA形式,。
原始出處:
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. ([email protected]) or P.S. (Email: [email protected]).
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.
