Safe, long-term hepatic expression of anti-HCV shRNA in a nonhuman primate model

David Suhy, Shih-Chu Kao, Tin Mao, Laurence Whiteley, Hubert Denise, Bernard Souberbielle, Andrew Burdick, Kyle Hayes, J. Fraser Wright, Helen Lavender, Peter Roelvink, Alexander Kolykhalov, Kevin Brady, Sterghios Moschos, Bernd Hauck, Olga Zelenaia, Shangzhen Zhou, Curt Scribner, Katherine High, Sara RenisonRomu Corbau

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45 Citations (Scopus)
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The hepatitis C virus (HCV) chronically infects 2% of the world population and effective treatment is limited by long duration and significant side-effects. Here, we describe a novel drug, intended as a "single-shot " therapy, which expresses three short hairpin RNAs (shRNAs) that simultaneously target multiple conserved regions of the HCV genome as confirmed in vitro by knockdown of an HCV replicon system. Using a recombinant adeno-associated virus (AAV) serotype 8 vector for delivery, comprehensive transduction of hepatocytes was achieved in vivo in a nonhuman primate (NHP) model following a single intravenous injection. However, dose ranging studies performed in 13 NHP resulted in high-expression levels of shRNA from wild-type (wt) Pol III promoters and dose-dependent hepatocellular toxicity, the first demonstration of shRNA-related toxicity in primates, establishing that the hepatotoxicity arises from highly conserved features of the RNA interference (RNAi) pathway. In the second generation drug, each promoter was re-engineered to reduce shRNA transcription to levels that circumvent toxicity but still inhibit replicon activity. In vivo testing of this modified construct in 18 NHPs showed conservation of hepatocyte transduction but complete elimination of hepatotoxicity, even with sustained shRNA expression for 50 days. These data support progression to a clinical study for treatment of HCV infection.
Original languageEnglish
Pages (from-to)1737-49
JournalMolecular therapy : the journal of the American Society of Gene Therapy
Issue number9
Early online date26 Jun 2012
Publication statusPublished - Sept 2012


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