Myd88 as a therapeutic target for choroidal neovascularization

Abstract

 

Purpose

 

Choroidal neovascularization (CNV), the hallmark of neovascular age-related macular degeneration (NV-AMD) is characterized by the invasion and leakage of choroidal blood vessels into neural retina. Recently we demonstrated that Myd88 dependent pathways mediate RPE degeneration in geographic atrophy, the other advanced form of AMD. Interestingly about 1/3rd of the GA patients are known to progress into NV-AMD. Therefore goal of the present study was to determine the role of Myd88 signaling pathways in the development of CNV.

 

Methods

 

CNV induction in mouse was performed following standard laser photocoagulation method. Choroidal angiogenesis volumes were measured by scanning laser confocal microscopy with 0.5% FITC-conjugated Isolectin B4. Activation of Myd88 signaling was assessed by examining the phosphorylation of IRAK4. Intraocular administration of neutralizing antibodies, cholesterol conjugated siRNAs and Myd88 inhibitory peptides was accomplished by intravitreous injection.

 

Results

 

The blockade of Myd88 signaling by genetic ablation, siRNA mediated knockdown or pharmacological intervention suppressed choroidal angiogenesis. Furthermore Myd88 activation in the mouse model of CNV was independent of TLR 2, 3, 4, 7 and 9. Inhibition of IRAK4, a signaling molecule downstream of Myd88, also suppressed laser induced CNV.

 

Conclusions

 

Our findings demonstrate that Myd88 mediated immune pathways play critical role in the mouse model of choroidal neovascularization. Therefore Myd88 offers a novel therapeutic target for neovascular AMD.

 

Keywords: 412 age-related macular degeneration