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

Mark E. Davis, Jonathan E. Zuckerman, Chung Hang J. Choi, David Seligson, Anthony Tolcher, Christopher A. Alabi, Yun Yen, Jeremy D. Heidel, Antoni Ribas

研究成果: 雜誌貢獻文章同行評審

1863 引文 斯高帕斯(Scopus)

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. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, 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. 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.

原文英語
頁(從 - 到)1067-1070
頁數4
期刊Nature
464
發行號7291
DOIs
出版狀態已發佈 - 四月 15 2010
對外發佈Yes

ASJC Scopus subject areas

  • General

指紋 深入研究「Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles」主題。共同形成了獨特的指紋。

引用此