《Nature》人类RNAi抗癌治疗临床一期试验取得成功

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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: mdavis@cheme.caltech.edu).

【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.

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