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      First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement.

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          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.

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          Author and article information

          Journal
          Cancer Discov
          Cancer discovery
          American Association for Cancer Research (AACR)
          2159-8290
          2159-8274
          Apr 2013
          : 3
          : 4
          Affiliations
          [1 ] Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. jtabernero@vhio.net
          Article
          2159-8290.CD-12-0429
          10.1158/2159-8290.CD-12-0429
          23358650
          99cb93f9-d4a1-44f6-afcb-15de3a7ea126
          ©2012 AACR.

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