《Nature》人类RNAi抗癌治疗临床一期试验取得成功

　　

生物通报道，加州技术学院化学工程系，David Geffen医学院病理系，造血与肿瘤研究系等多处的研究人员在RNAi治疗潜能的证实方面取得新的进展，相关成果文章Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles公布在最新一期的Nature杂志上，首次在人类RNAi临床试验上取得成果。

 

自1998年Andrew Z. Fire首次成功应用RNAi技术以来，科学家们就对RNAi寄予厚望。RNAi可随意沉默基因组中的基因，因此具有广阔的应用空间。2006年，RNAi技术的首创者Andrew Z. Fire也因此获得2006年的诺贝尔奖。

 

现在，Davis等人又首次在人类中发现，一个“短干涉RNA分子”（siRNA）可以利用纳米颗粒被系统性提供给一个固体肿瘤。目前该实验已经进入临床一期试验阶段，Davis研究小组用一个纳米颗粒传递系统将siRNA转运到固体肿瘤癌细胞内，通过肿瘤组织活检来检查这个纳米传递系统的有效性。

 

研究人员在肿瘤组织活检过程中还发现，细胞中的目标蛋白RRM2的信使RNA表达量降低，同时，RRM2蛋白的表达量也降低。为了检测RNAi的效率，研究人员还在肿瘤细胞中检测到含有大量纳米颗粒的部位存在大量信使RNA片段。

 

这一已经进入临床一期试验的数据结果表明，纳米传递系统有效，接受RNAi治疗的患者目标基因的信使RNA和目标基因的蛋白表达量都显著降低，完全证实RNAi可以在临床上有效地应用，成为一种可抑制目标基因的有效治疗手段。

（生物通 张欢）

microRNA发现与验证一站式解决方案

生物通推荐原文检索

Nature 464, 1067-1070 (15 April 2010) | doi:10.1038/nature08956; Received 23 September 2009; Accepted 1 March 2010; Published online 21 March 2010

 

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.