Abstract
RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof-of-concept for RNAi therapeutics in humans and form the basis for further development in cancer. The fi ndings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel fi rst-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specifi c multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology.
Highlights
RNA interference (RNAi) is an endogenous cellular mechanism for controlling gene expression in which siRNAs bound to RNA-induced silencing complex (RISC) mediate target mRNA cleavage and degradation through a catalytic process involving the Argonaute 2 endonuclease [1, 2]
Distribution to tumors with leaky microvasculature containing endothelial pores is thought to occur through the enhanced permeability and retention (EPR) mechanism described for liposomes and other nanoparticles [23, 24]
The 2 siRNAs were chemically modified with 2′-O-methyl groups to minimize immunostimulation through RNA sensor pathways including Toll-like receptor (TLR) [18,19,20], it is possible that either the siRNAs or one or more of the lipid components were involved in proinflammatory cytokine induction
Summary
RNA interference (RNAi) is an endogenous cellular mechanism for controlling gene expression in which siRNAs bound to RNA-induced silencing complex (RISC) mediate target mRNA cleavage and degradation through a catalytic process involving the Argonaute 2 endonuclease [1, 2]. Because the RNAi pathway is present in all mammalian cell types, the primary challenge for effective gene silencing in vivo is delivery of the siRNA to the appropriate organ(s) with productive cellular uptake leading to engagement of RISC in the cytosol. Various nanoparticle formulations have been evaluated for their ability to silence targets in vivo [6,7,8,9,10]; among these, lipid nanoparticles (LNP) have been shown to be highly effective in delivering siRNAs to the liver and silencing a number of different hepatocyte gene targets across multiple species, including rodents and nonhuman primates [11,12,13,14]. Results in animal models with LNPs are promising, it remains to be shown whether these findings will translate into an effective way to deliver siRNAs for the treatment of human disease. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated the first phase I trial using this approach to treat patients with advanced cancer and liver metastases
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