Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles

被引:1925
作者
Davis, Mark E. [1 ]
Zuckerman, Jonathan E. [1 ]
Choi, Chung Hang J. [1 ]
Seligson, David [2 ,3 ]
Tolcher, Anthony [5 ]
Alabi, Christopher A. [1 ]
Yen, Yun [6 ]
Heidel, Jeremy D. [7 ]
Ribas, Antoni [2 ,4 ]
机构
[1] CALTECH, Pasadena, CA 91125 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA
[5] START LLC, San Antonio, TX 78229 USA
[6] City Hope Comprehens Canc Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA
[7] Calando Pharmaceut, Pasadena, CA 91101 USA
关键词
RIBONUCLEOTIDE REDUCTASE; GENE-EXPRESSION; IN-VIVO; INTERFERENCE; POTENT; MICE; CELL; PHARMACOKINETICS; THERAPEUTICS; INHIBITION;
D O I
10.1038/nature08956
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients(1,2). 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 response(4). 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.
引用
收藏
页码:1067 / U140
页数:5
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