Unknown

Dataset Information

0

Sequence- and target-independent angiogenesis suppression by siRNA via TLR3.


ABSTRACT: Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 (also called FLT1), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNA interference (RNAi). We show instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNAs targeting Vegfa or Vegfr1 without off-target RNAi or interferon-alpha/beta activation. Non-targeted (against non-mammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell-surface toll-like receptor 3 (TLR3), its adaptor TRIF, and induction of interferon-gamma and interleukin-12. Non-targeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modelled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects.

SUBMITTER: Kleinman ME 

PROVIDER: S-EPMC2642938 | BioStudies | 2008-01-01

REPOSITORIES: biostudies

Similar Datasets

2009-01-01 | S-EPMC2678451 | BioStudies
2015-01-01 | S-EPMC4881762 | BioStudies
2020-01-01 | S-EPMC7563259 | BioStudies
2013-01-01 | S-EPMC3748119 | BioStudies
2020-01-01 | S-EPMC7053208 | BioStudies
2019-01-01 | S-EPMC6393707 | BioStudies
2019-01-01 | S-EPMC6701410 | BioStudies
1000-01-01 | S-EPMC3255577 | BioStudies
2014-01-01 | S-EPMC3905033 | BioStudies
1000-01-01 | S-EPMC3812658 | BioStudies