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

By Mark E. Davis, J. Zuckerman, C. H. J. Choi, D. Seligson, A. Tolcher, Christopher A. Alabi, Y. Yen, J. Heidel, Antoni Ribas. Nature, 2010

2,430 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/323b77c043cb35abe50fe67b0b576b0c5e7e3d75

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Citations in the corpus

An overview of active and passive targeting strategies to improve the nanocarriers efficiency to tumour sites (2019, background): “The first evidence of RNA interference in humans was shown with targeted nanoparticles.([95]) On the other hand, cyclodextrin-based polymer functionalized with free PEG and PEG-transferrin conjugates.”
Nanomedicine in cancer therapy (2023, background): “252 255 Furthermore, a variety of cell adhesion proteins which include cadherins, integrins, and selectins can also be utilized to deliver nanoparticles to speci ﬁ c targets located in the cancer cell membrane.”
The delivery of therapeutic oligonucleotides (2016, background): “Although they have not progressed clinically to the same degree as LNPs, it is worth noting that the first use of siRNA to treat human cancer involved a ligand-targeted cyclodextrin-based polymeric nanoparticle (192).”
Apoptosis and Molecular Targeting Therapy in Cancer (2014, background): “Importantly, data from this trial demonstrated, for the first time, that systemically delivered siRNA can reduce protein levels of a specific gene through an RNAi mechanism in humans [264].”
Nanoparticles in the clinic (2016, methodology): “This system used a cyclodextrinbased particle which contained PEG, an siRNA designed to knockdown RRM2, and a transferrin receptor targeting protein, which when formulated together in a single nanoparticle was successful in achieving knockdown of the protein RRM2 (Figure 2ai).(60,61) A similar strat”
Dragging ras back in the ring. (2014, background): “…that completely different approaches to treating cancer will contribute to eliminating Ras cancers, including new ways of knocking down/out genes using RNAi and CRISPR technologies and delivering these payloads to tumors (Davis et al., 2010), as well as new ways of deploying the immune system.”