Editors' ChoiceNanotechnology

Giving Tumors the Silent Treatment

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Science Translational Medicine  31 Mar 2010:
Vol. 2, Issue 25, pp. 25ec50
DOI: 10.1126/scitranslmed.3001098

When Fire and Mello were awarded the 2006 Nobel Prize in Physiology or Medicine for the discovery of RNA interference (RNAi), this powerful technology to study gene function took center stage. RNAi’s mechanism is based on the fact that when a single-stranded small-interfering RNA (siRNA) is introduced into cells and binds to a complementary single-stranded mRNA sequence from a transcribed gene, that double-stranded RNA is rapidly degraded, thus silencing the corresponding gene. Indeed, siRNAs have successfully silenced selected genes in cell lines and animal models through RNAi; however, siRNAs can also quiet genes through other nonspecific mechanisms. Therefore, until the recent report by Davis et al., it was unclear whether siRNAs administered to human patients would be capable of silencing disease-promoting genes through RNAi.

In a first-in-human phase I clinical trial, the authors introduced siRNAs systemically, using a nanoparticle delivery system. The siRNAs were directed against the RRM2 gene, which encodes a ribonucleotide reductase that functions in DNA synthesis and is an important therapeutic target for cancers. Armed with pre- and posttreatment tumor biopsy samples from patients with melanoma skin cancers, the authors demonstrated the following dose-dependent effects in tumor cells: (i) accumulation of the siRNA nanoparticles, (ii) reduced RRM2 mRNA and protein concentrations, and (iii) increased RRM2 mRNA degradation products, all of which indicated that RNAi was the mechanism of target gene silencing.

This proof-of-principle trial demonstrates the feasibility and utility of targeting myriad disease-causing genes with RNAi technology. Although these results are exciting, researchers must begin to anticipate possible resistance mechanisms associated with RNAi so that many other diseases may be given the silent treatment.

M. E. Davis et al., Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 21 March 2010 (10.1038/nature08956). [Full Text]

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