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

Suhy, David, Kao, Shih-Chu, Mao, Tin, Whiteley, Laurence, Denise, Hubert, Souberbielle, Bernard, Burdick, Andrew, Hayes, Kyle, Wright, J. Fraser, Lavender, Helen, Roelvink, Peter, Kolykhalov, Alexander, Brady, Kevin, Moschos, Sterghios, Hauck, Bernd, Zelenaia, Olga, Zhou, Shangzhen, Scribner, Curt, High, Katherine, Renison, Sara and Corbau, Romu (2012) Safe, long-term hepatic expression of anti-HCV shRNA in a nonhuman primate model. Molecular therapy : the journal of the American Society of Gene Therapy, 20 (9). pp. 1737-49. ISSN 1525-0024

[img]
Preview
Text (Article)
mt2012119a.pdf - Published Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (2MB) | Preview
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
Subjects: A300 Clinical Medicine
B200 Pharmacology, Toxicology and Pharmacy
C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > School of Life Sciences > Applied Sciences
Depositing User: Sterghios Moschos
Date Deposited: 24 Oct 2016 08:46
Last Modified: 24 Oct 2016 08:51
URI: http://nrl.northumbria.ac.uk/id/eprint/28134

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year

View more statistics


Policies: NRL Policies | NRL University Deposit Policy | NRL Deposit Licence