Sequence- and target-independent angiogenesis suppression by siRNA via TLK3 (Nature, 2008, 452:591-597)

報告日期: 2008/12/23
報告時間: 17:05/17:55
報告學生: 林韋伶
講評老師: 張文粲
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/971223-3.pdf

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

Mark E. Kleinman, Kiyoshi Yamada, Atsunobu Takeda, et al.

Nature 452, 591-598 (2008)

 

Speaker: 林韋伶

Commentator: 張文粲老師

Time: 2008/12/23 AM 17:05

Place: Room 602

 

Abstract

Angiogenesis is the process of the formation of new blood vessels from a pre-existing capillary network and occurs in patients with the choroidal neovascularization (CNV). CNV is the late stage of age-related macular degeneration1 which is a leading cause of irreversible blindness among people who over 50 years of age in the developed world. In clinical, blockage of vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 with antibodies has been approved to suppress angiogenesis in CNV patients. Furthermore, VEGFA or VEGFR1 siRNA has been reported that such siRNAs inhibited laser-injury-induced CNV in mice2,3. In this paper, however, the authors found that the anti-angiogenic effect could be induced by non-targeted siRNAs that vary significantly in sequence. These siRNAs acted through the Toll-like receptor -3 (TLR3), an immune system regulator present on the surface of many cells. The results showed that both non-targeted and targeted siRNAs induced TLR3 activation involved TRIF- NF-κB cascade. Consequently, genes encoding interferon-γ(IFN-γ) and interleukin-12 (IL-12) , which are the agents of anti-angiogenesis, were expressed. However, the phenomenon was not observed in Tlr3-/- mice. Additionally, a siRNA had to be at least 21 nucleotides in length to have anti-angiogenic activity through TLR. The authors’ structural analysis showed that 21 nucleotides are required for proper docking on TLR3 and its activation through receptor dimerization on the cell surface. In clinical implication, they provided the results that non-targeted and targeted siRNAs would be have different efficacy on individuals with a particular single nucleotide polymorphism in TLR3. Such genotypic variance could be exploited to identify individuals for appropriate siRNA therapies.

 

1.   Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nature Rev. Drug Discov. 6, 273286 (2007).

2.   Reich, S. J. et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol. Vis. 9, 210–216 (2003).

3.   Shen, J. et al. Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther. 13, 225–234 (2006).