Projects and Grants per year
Grants and Contracts Details
Description
The discovery of RNA interference (RNAi) and its potential to silence any gene of interest via
the RNA-induced silencing complex (RISC) has revolutionized modern genetics and launched a
new class of therapeutics termed short interfering RNA (siRNA). The first clinical trials of siRNA
were initiated in patients with choroidal neovascularization (CNV) due to age-related macular
degeneration (AMD), which is the leading cause of blindness among the elderly in industrialized
world and afflicts more people in the United States than all cancers combined. In new and
exciting recent work, we made the surprising discovery that siRNAs uniformly suppress
experimental CNV in mice, independent of RNAi. We found that that siRNAs against nonmammalian
genes, genes not expressed in the eye, or random sequences without homology to
any known gene, all suppressed CNV, as did a modified siRNA incapable of RISC
incorporation. This novel class effect was mediated via activation of toll like receptor-3 (TLR3)
and its adaptor protein TRIF, and induction of interferon-y and interleukin-12. Interestingly,
siRNAs targeting vascular endothelial growth factor (VEGF)-A or its receptor VEGFR-1, which
are in Phase II clinical trials, also suppressed CNV via TLR3 activation and not cognate
transcript knockdown. We will test the hypothesis that both targeted and non-targeted siRNAs
activate TLR3 by direct interaction and trigger a cellular program of vascular growth
suppression. The specific aims of this proposal are to further define the interaction between
siRNA and TLR3, determine the precise anti-angiogenic mechanisms of siRNA-induced CNV
suppression in mice, and test the efficacy of non-targeted siRNA in a non-human primate model
of CNV. These studies will provide clarifying insights into the mechanisms underlying
unanticipated siRNA activities in vivo, define the molecular architecture governing this
intersection of vascular biology and innate immunity, provide pharmacogenetic data that will
enable personalized medicine in patients with TLR3 mutations, and propel the development of
new, more affordable anti-angiogenic therapeutics for the public health epidemic that is AMD.
Status | Finished |
---|---|
Effective start/end date | 4/1/08 → 3/31/13 |
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Projects
- 1 Finished
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Intrinsic Anti-Angiogenic Activity of siRNA - Supplemental - Equipment
Ambati, J. (PI)
4/1/08 → 3/31/11
Project: Research project