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 (LNPs) have proven effective in delivery of siRNAs to liver and tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in man, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and KSP, in cancer patients. Here we demonstrate detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in liver, pharmacodynamics suggestive of target downregulation, and antitumor activity including complete regression of liver metastases in endometrial cancer. In addition, we show that bi-weekly intravenous administration of ALN-VSP was safe and well-tolerated. These data provide proof of concept for RNAi therapeutics in man and form the basis for further development in cancer.
- Received September 24, 2012.
- Revision received December 26, 2012.
- Accepted January 24, 2013.
- Copyright © 2013, American Association for Cancer Research.