《Nature》RNAi关闭癌基因

　　

生物通报道，RNAi的发现让科学家们多一种人为控制基因表达的手段，也因此RNAi发现者获得2006年诺奖，然而RNAi治疗性的研究却进展不大，主要因为科学家目前还没有找到一个将RNAi分子完美地递送到靶位的技术，不过来自加州技术学院，Jonsson综合癌症研究中心的科学家取得了突破，他们尝试用siRNA阻断皮肤癌基因，相关成果文章Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles公布在Nature在线版上。

 

RNA能够充当“信使”，传递DNA（脱氧核糖核酸）上的遗传信息，将其用于蛋白质的生产合成。研究显示，向生物体内注入siRNA片段，会干扰生物体本身的RNA“信使”功能，导致相应蛋白质无法合成，从而“关闭”特定基因。

 

为了解决传递siRNA分子的难题，科学家们开发了一套纳米载体系统，将目标siRNA传递到癌细胞上，目前，这一技术已经进入临床一期试验期。

 

该研究主要针对黑色素瘤，这套纳米载体系统可以成功地将siRNA传递给癌细胞，科学家们取受试者的瘤组织进行检测，发现大量的纳米载体系统。

 

为了验证这个传导系统和siRNA是否对癌细胞有专嗜性，科学家们又取了正常组织，结果发现，瘤组织中的RRM2信使RNA表达量和RRM2蛋白表达量均比正常组织的低，这表明siRNA正在发挥RNAi的作用。

 

这个纳米载体系统约为70纳米大，可携带阻断RRM2的siRNA进入血液循环系统中，随后进入癌变组织，值得关注的是，免疫系统对纳米载体没有攻击性，并且纳米载体释放阻断RRM2的siRNA后，纳米载体也随之进入尿液中被排出。

 

科学家们认为，这个纳米载体十分有效，他们将尝试用其携带其他的siRNA治疗其他癌症。

（生物通 小茜）

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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.

Correspondence to: Mark E. Davis1 Correspondence and requests for materials should be addressed to M.E.D. (Email: [e-mail]).

 

【Abstract】

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.