首次实现利用RNAi治疗癌症

导读：这种携带了特定RNA的载体进入血液后，不会引起免疫系统的排异反应，可随着血液流动到达发生癌变的部位，然后进入癌细胞释放出RNA，而剩下的载体物质由于太过微小可随着尿液排出。

美国加州理工学院等机构的研究人员报告说，他们合成了一种直径仅为70纳米的微小载体。这种携带了特定RNA的载体进入血液后，不会引起免疫系统的排异反应，可随着血液流动到达发生癌变的部位，然后进入癌细胞释放出RNA，而剩下的载体物质由于太过微小可随着尿液排出。

该研究发表于3月21日 英国《自然》杂志网站研究报告上，美国研究人员成功利用纳米级别的微小载体将特定的RNA（核糖核酸）送达人体癌变部位，从而干扰了癌细胞的基因并起到治疗作用。

RNA是基因指导合成蛋白质的过程中所必需的工具，这段人为添加的RNA可以干扰癌细胞中原有RNA的作用，使其不能合成相应的蛋白质。在试验中，研究人员对患有皮肤癌的病人使用了这项新技术，结果发现它可以精确阻碍名为RRM2的目标基因发挥作用，使得患者癌细胞中相应的蛋白质减少，从而起到治疗癌症的作用。

研究人员马克·戴维斯说，通过选择所使用的RNA，这项技术可以阻碍任何基因发挥作用，因此有望用于广泛治疗各种癌症。

这是首次实现在人体中利用RNA干扰来治疗癌症的研究。外加RNA可以阻止特定基因发挥作用的现象称为“RNA干扰”，由安德鲁·法尔和克雷格·梅洛在上世纪90年代发现，他们因此荣获2006年诺贝尔生理学或医学奖


Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles
Mark E. Davis1, Jonathan E. Zuckerman1, Chung Hang J. Choi1, David Seligson2,3, Anthony Tolcher5, Christopher A. Alabi1,8, Yun Yen6, Jeremy D. Heidel7 & Antoni Ribas2,4

Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
Jonsson Comprehensive Cancer Center,
Department of Pathology, David Geffen School of Medicine,
Department of Medicine, Division of Hematology Oncology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
START - South Texas Accelerated Research Therapeutics, LLC, 4383 Medical Drive, 4th Floor, San Antonio, Texas 78229, USA
Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, California 91010, USA
Calando Pharmaceuticals, 201 South Lake Avenue, Suite 703, Pasadena, California 91101, USA
Present address: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients1, 2. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans 3, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response4. We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.