? West Nile (WN) and Japanese encephalitis (JE) viruses are flaviviruses that can cause a devastating acute neurological illness and currently there is no effective treatment for these viral infections. We have developed a RNA interference-based therapeutic method to suppress these viruses and shown the feasibility of using a single siRNA as a broad-spectrum antiviral agent to suppress fatal infections caused by both WNV and JEV in mice. However, the major challenge for harnessing the potential of siRNA for human therapy is the lack of suitable delivery methods. Delivery is particularly difficult in the CNS because of the presence of the blood-brain barrier. Preliminary studies suggest that a small peptide derived from the Rabies virus glycoprotein (RVG) may allow neuronal cell-specific targeting. Remarkably, when fused to a positively charged polymeric arginine peptide, the chimeric RVG-9R peptide was able to bind siRNA (by charge interaction) and deliver the siRNA to brain cells after intravenous injection in mice, resulting in specific gene silencing in the brain. Thus, we have identified a potential """"""""siRNA drug"""""""" to treat flaviviral encephalitis as well as developed a clinically feasible method of delivering it to the brain by simple intravenous injection. ? In this proposal, in association with Alnylam Pharmaceuticals Inc, we will conduct preclinical evaluation of efficacy and safety, and advance the product development towards human therapy. Specifically, in aim1, we will conduct a comprehensive screen to select the most potent 2-3 lead antiviral siRNAs and chemically modify them for proper drug-like properties.
In aim 2 we will address the bioavailability and safety/toxicology issues and determine the specificity of RNAi effects.
In aim 3, we will test the efficacy of intravenous treatment to suppress encephalitis induced by JEV and WNV, both before and at different times after infection. To enhance the therapeutic index and safety of this treatment approach, in Aim 4 we will develop several different formulations of siRNA/peptide complex using RVG as the neuronal targeting agent. ? ? Relevance: ? These studies are expected to lead to the development of a viable RNAi-based treatment strategy for viral encephalitis. In addition, we would have developed a transvascular method for CNS delivery of siRNA and potentially other therapeutic agents that would facilitate treatment of a variety of neurological diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
7U01AI075419-02
Application #
7475259
Study Section
Special Emphasis Panel (ZAI1-MH-M (M2))
Program Officer
Tseng, Christopher K
Project Start
2007-08-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$849,005
Indirect Cost
Name
Texas Tech University
Department
Type
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
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Ye, C; Bhan, A K; Deshpande, V et al. (2013) Silencing TNF-? in macrophages and dendritic cells for arthritis treatment. Scand J Rheumatol 42:266-9
Ye, Chunting; Choi, Jang-Gi; Abraham, Sojan et al. (2012) Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model. Proc Natl Acad Sci U S A 109:21052-7
Chen, Shuiping; Chahar, Harendra S; Abraham, Sojan et al. (2011) Ago-2-mediated slicer activity is essential for anti-flaviviral efficacy of RNAi. PLoS One 6:e27551
Wu, Haoquan; Ma, Hongming; Ye, Chunting et al. (2011) Improved siRNA/shRNA functionality by mismatched duplex. PLoS One 6:e28580
Ye, Chunting; Abraham, Sojan; Wu, Haoquan et al. (2011) Silencing early viral replication in macrophages and dendritic cells effectively suppresses flavivirus encephalitis. PLoS One 6:e17889
Manjunath, N; Dykxhoorn, Derek M (2010) Advances in synthetic siRNA delivery. Discov Med 9:418-30
Kim, Sang-Soo; Ye, Chunting; Kumar, Priti et al. (2010) Targeted delivery of siRNA to macrophages for anti-inflammatory treatment. Mol Ther 18:993-1001
Subramanya, Sandesh; Kim, Sang-Soo; Abraham, Sojan et al. (2010) Targeted delivery of small interfering RNA to human dendritic cells to suppress dengue virus infection and associated proinflammatory cytokine production. J Virol 84:2490-501
Subramanya, Sandesh; Kim, Sang-Soo; Manjunath, N et al. (2010) RNA interference-based therapeutics for human immunodeficiency virus HIV-1 treatment: synthetic siRNA or vector-based shRNA? Expert Opin Biol Ther 10:201-13

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