来自Alnylam公司，美国麻省理工癌症研究中心（Center for Cancer Research），德州大学西南医学中心（University of Texas Southwestern Medical Center），瑞士联邦技术院（Swiss Federal Institute of Technology Zurich， ETHZ）的研究人员证实了一种深
具潜力的遗传治疗方法的安全性，这种治疗方法有广泛的应用前景，可以治疗包括癌症在内的许多疾病。
这一研究成果公布在9月27日的Nature杂志上，文章描述了一种治疗的新方法，去年一篇同样发表于Nature的文章报道了另外一种常用的的方法，但是这种方法会引起小鼠致死。
在Anderson等人发表这篇新成果中，研究人员证实siRNA并不会如同shRNA一样，加大剂量引起毒性，这是因为这一过程并不会影响miRNA途径，而且研究人员在小鼠
和仓鼠肝脏细胞中实现了靶标基因80％的沉默效果。
Alnylam科研主任David Bumcrot表示，“利用化学合成的siRNA，你可以传递有效siNRA，获得治疗性的基因沉默效果，而这并不影响细胞内源性miRNA”。
研究人员采用的RNA传递系统是来自麻省理工的一种RNA传递新方法，这种方法的具体细节将于另外一篇文章中公布。
在许多RNAi研究中，研究人员都是利用逆转录病毒传递编码shRNA的基因，进一步加工成siRNA，一旦这一基因结合到细胞DNA上，shRNA就会合成，从细胞核传递到细胞质。早期的研究发现大量shRNA会阻断细胞输出miRNA，因为后者与前者使用的是同一输出途径。没有正常的功能性miRNAs，小鼠就会死亡。虽然低剂量的shRNA不会引起毒性，但是这种剂量很难进行调控——一旦shNRA基因结合到宿主细胞DNA上，它的表达期限就很长。
这篇文章则是将siRNA直接传递到细胞质，因此不会与miRNA形成竞争。Bumcrot认为，“我们希望证明如果是在这一途径的下游进行，那么就不会干扰miRNA途径”，“利用合成的siRNA，我们传递了一个合适剂量的siRNA，我们知道这种效果会持续多久，如果产生毒性，可以马上停止，因此这样比较容易调控，安全一些。”
原始出处:
Nature advance online publication 26 September 2007 | doi:10.1038/nature06179; Received 17 November 2006; Accepted 16 August 2007; Published online 26 September 2007
Effective RNAi-mediated gene silencing without interruption of the endogenous microRNA pathway
Matthias John1, Rainer Constien1, Akin Akinc2, Michael Goldberg3, Young-Ah Moon5, Martina Spranger6, Philipp Hadwiger1, Jürgen Soutschek1, Hans-Peter Vornlocher1, Muthiah Manoharan2, Markus Stoffel6, Robert Langer3,4, Daniel G. Anderson4, Jay D. Horton5, Victor Koteliansky2 & David Bumcrot2
Alnylam Europe AG, Fritz-Hornschuch-Str. 9, 95326 Kulmbach, Germany
Alnylam Pharmaceuticals Inc., 300 Third Street, Cambridge, Massachusetts 02142, USA
Department of Chemistry, and,
Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetss 02139, USA
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA
Institute of Molecular Systems Biology, Swiss Federal Institute of Technology ETH Zürich, HPT E73, CH-8093 Zürich, Switzerland
Correspondence to: David Bumcrot2 Correspondence and requests for materials should be addressed to D.B. (Email: dbumcrot@alnylam.com).
Systemic administration of synthetic small interfering RNAs (siRNAs) effectively silences hepatocyte gene expression in rodents and primates1, 2, 3. Whether or not in vivo gene silencing by synthetic siRNA can disrupt the endogenous microRNA (miRNA) pathway remains to be addressed. Here we show that effective target-gene silencing in the mouse and hamster liver can be achieved by systemic administration of synthetic siRNA without any demonstrable effect on miRNA levels or activity. Indeed, siRNA targeting two hepatocyte-specific genes (apolipoprotein B and factor VII) that achieved efficient (80%) silencing of messenger RNA transcripts and a third irrelevant siRNA control were administered to mice without significant changes in the levels of three hepatocyte-expressed miRNAs (miR-122, miR-16 and let-7a) or an effect on miRNA activity. Moreover, multiple administrations of an siRNA targeting the hepatocyte-expressed gene Scap in hamsters achieved long-term mRNA silencing without significant changes in miR-122 levels. This study advances the use of siRNAs as safe and effective tools to silence gene transcripts in animal studies, and supports the continued advancement of RNA interference therapeutics using synthetic siRNA.
