Abstract

RNAi based therapeutics offers great promise for a myriad of diseases. The Kay laboratory has successfully used an AAV vector-based approach to express shRNAs from liver. We have established that such vectors can safely and persistently reduce Hepatitis B viral (HBV) replication by 2 to 3 logs in HBV transgenic mice. Nonetheless, we have established that over expression of some shRNAs can result in fatality due to liver failure. Liver failure was associated with interference in the endogenous microRNA processing pathway and at least part of the block was at the level of Exportin-5. The Rossi laboratory has developed alternative shRNA expression strategies some of which bypass the Exportin-5 pathway. The two labs together offer a synergistic approach such that in the proposed consortium, they will work together to further unravel the mechanisms involved in shRNA based toxicities as well as develop new expression paradigms for in vivo shRNA based therapeutics. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078424-02
Application #
7290342
Study Section
Special Emphasis Panel (ZRG1-BST-Z (52))
Program Officer
Serrano, Jose
Project Start
2006-09-30
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$325,280
Indirect Cost

  Institution

Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Valdmanis, Paul N; Kim, Hak Kyun; Chu, Kirk et al. (2018) miR-122 removal in the liver activates imprinted microRNAs and enables more effective microRNA-mediated gene repression. Nat Commun 9:5321
Valdmanis, Paul N; Kay, Mark A (2017) Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond. Hum Gene Ther 28:361-372
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
Chak, Kayam; Roy-Chaudhuri, Biswajoy; Kim, Hak Kyun et al. (2016) Increased precursor microRNA-21 following status epilepticus can compete with mature microRNA-21 to alter translation. Exp Neurol 286:137-146
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
Chung, Janet; Scherer, Lisa J; Gu, Angel et al. (2014) Optimized lentiviral vectors for HIV gene therapy: multiplexed expression of small RNAs and inclusion of MGMT(P140K) drug resistance gene. Mol Ther 22:952-63
Gu, Shuo; Jin, Lan; Huang, Yong et al. (2012) Slicing-independent RISC activation requires the argonaute PAZ domain. Curr Biol 22:1536-42
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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