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

Suhy, David A. and Kao, Shih-Chu and Mao, Tin and Whiteley, Laurence and Denise, Hubert and Souberbielle, Bernard and Burdick, Andrew D. and Hayes, Kyle and Wright, J. Fraser and Lavender, Helen and Roelvink, Peter and Kolykhalov, Alexander and Brady, Kevin and Moschos, Sterghios A. and Hauck, Bernd and Zelenaia, Olga and Zhou, Shangzhen and Scribner, Curt and High, Katherine A. and Renison, Sara H. and Corbau, Romu (2012) Safe, long-term hepatic expression of anti-HCV shRNA in a nonhuman primate model. Molecular Therapy, 20 (9). pp. 1737-1749. ISSN 1525-0016

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Official URL: http://dx.doi.org/10.1038/mt.2012.119

Abstract

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.

Item Type:Article
Research Community:University of Westminster > Life Sciences, School of
ID Code:10852
Deposited On:19 Jul 2012 11:46
Last Modified:24 Jun 2013 16:49

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