Hepatitis virus infection remains a major health issue throughout the world. Although there are effective drugs and a vaccine for hepatitis B (HBV) infection, there are almost 200,000,000 people infected worldwide. It is estimated that 2 to 4% of Americans are infected with Hepatitis C Virus Infection (HCV), and it is the leading indication for liver transplantation in the western world. For HCV infection, interferon/Ribavarin therapy is expensive, difficult, and not effective in a majority of cases. New small molecule drugs are being developed, but they target a specific protein resulting in the emergence of infectious HCV quasi-species, leading to quick resistance to the therapeutic. RNA interference (RNAi) is a powerful new approach to turning off genes in cells, making it an alternative therapeutic approach to treat infectious processes. Moreover, strategies can be designed to minimize the possibility of escape mutant formation. We have had preliminary success in using a new AAV vector to achieve a safe and sustained >100 times reduction in HBV replication in a transgenic mouse model. Interestingly, we have come across some interesting biological responses to overexpression of shRNA in vivo. Our approach is to develop an RNAi gene therapeutic that would be useful for treating hepatitis virus infection. To do this we will: (1) continue to use a mouse model of HBV to study basic biological responses to shRNA expression in vivo;(2) develop robust shRNA expression sequences against HCV;and (3) test novel AAV shRNA expression cassettes in a bona-fide mouse model of HCV replication in vivo. We believe the data generated during the granting period will develop the reagents necessary to pursue a Phase I clinical trial for HCV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI071068-04S1
Application #
8045679
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Koshy, Rajen
Project Start
2010-04-12
Project End
2011-03-31
Budget Start
2010-04-12
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$183,150
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Kim, Hak Kyun; Fuchs, Gabriele; Wang, Shengchun et al. (2017) A transfer-RNA-derived small RNA regulates ribosome biogenesis. Nature 552:57-62
Valdmanis, Paul N; Gu, Shuo; Chu, Kirk et al. (2016) RNA interference-induced hepatotoxicity results from loss of the first synthesized isoform of microRNA-122 in mice. Nat Med 22:557-62
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Valdmanis, P N; Roy-Chaudhuri, B; Kim, H K et al. (2015) Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma. Oncogene 34:94-103
Gu, Shuo; Zhang, Yue; Jin, Lan et al. (2014) Weak base pairing in both seed and 3' regions reduces RNAi off-targets and enhances si/shRNA designs. Nucleic Acids Res 42:12169-76
Roy-Chaudhuri, Biswajoy; Valdmanis, Paul N; Zhang, Yue et al. (2014) Regulation of microRNA-mediated gene silencing by microRNA precursors. Nat Struct Mol Biol 21:825-32
Gu, Shuo; Jin, Lan; Zhang, Yue et al. (2012) The loop position of shRNAs and pre-miRNAs is critical for the accuracy of dicer processing in vivo. Cell 151:900-911
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Grimm, Dirk; Wang, Lora; Lee, Joyce S et al. (2010) Argonaute proteins are key determinants of RNAi efficacy, toxicity, and persistence in the adult mouse liver. J Clin Invest 120:3106-19

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