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

Davis, Mark E. and Zuckerman, Jonathan E. and Choi, Chung Hang J. and Seligson, David and Tolcher, Anthony and Alabi, Christopher A. and Yen, Yun and Heidel, Jeremy D. and Ribas, Antoni (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature, 464 (7291). pp. 1067-1071. ISSN 0028-0836. PMCID PMC2855406. doi:10.1038/nature08956.

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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.

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Davis, Mark E.0000-0001-8294-1477
Alabi, Christopher A.0000-0003-2654-018X
Yen, Yun0000-0003-0815-412X
Additional Information:© 2010 Macmillan Publishers Limited. Received 23 September 2009; accepted 1 March 2010. Published online 21 March 2010. We thank H. Sazegar, E. Seja, A. Villanueva and the G-CRC nursing staff at University of California, Los Angeles (UCLA), and L. Kalinoski, J. Peterkin, S. Rele, Y. Liang and J. Y. C. Liu for their assistance in conducting the clinical trial. We thank J. S. Economou for performing the tumour biopsies, and B. Chmielowski and Z. Wainberg for patient referrals. Histotechnology support at the UCLA Biomarker Innovations Laboratory was provided by C. Savina and J. Reiss. We also thank J. Rossi for discussions on RACE analyses. This work was supported in part by the National Cancer Institute Grant CA U54 119347 and the Daljit S. & Elaine Sarkaria Biomarker Laboratory Fund. Author Contributions: M.E.D., J.E.Z., A.R. and J.D.H. planned the experiments, J.E.Z., D.S., C.H.J.C., C.A.A., Y.Y., A.T. and A.R. conducted the experiments, M.E.D., J.E.Z., J.D.H., D.S., C.H.J.C. and A.R. analysed the data, and M.E.D., J.E.Z. and A.R. wrote the paper.
Funding AgencyGrant Number
NIHCA U54 119347
Daljit S. & Elaine Sarkaria Biomarker Laboratory FundUNSPECIFIED
National Cancer InstituteUNSPECIFIED
Issue or Number:7291
PubMed Central ID:PMC2855406
Record Number:CaltechAUTHORS:20100512-155357114
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Official Citation: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 Nature 464, 1067-1070(15 April 2010) doi:10.1038/nature08956
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:18278
Deposited By: Tony Diaz
Deposited On:14 May 2010 23:19
Last Modified:08 Nov 2021 23:42

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