TY - JOUR
T1 - Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles
AU - Davis, Mark E.
AU - Zuckerman, Jonathan E.
AU - Choi, Chung Hang J.
AU - Seligson, David
AU - Tolcher, Anthony
AU - Alabi, Christopher A.
AU - Yen, Yun
AU - Heidel, Jeremy D.
AU - Ribas, Antoni
N1 - Funding Information:
Acknowledgements 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.
PY - 2010/4/15
Y1 - 2010/4/15
N2 - 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.
AB - 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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U2 - 10.1038/nature08956
DO - 10.1038/nature08956
M3 - Article
C2 - 20305636
AN - SCOPUS:77951132901
SN - 0028-0836
VL - 464
SP - 1067
EP - 1070
JO - Nature
JF - Nature
IS - 7291
ER -