VE-PTP potential treatment target for retinal and choroidal vascular diseases

Dec 1 2014

By Lucy Piper, Senior medwireNews Reporter

Targeting vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, could help to stabilise retinal and choroidal blood vessels, researchers report.

This could provide an alternative treatment method to intraocular injections of anti-vascular endothelial growth factor (VEGF), which for chronic diseases such as neovascular age-related macular degeneration (AMD) and diabetic macular oedema, often need to be repeated for many years, they say.

Researcher Peter Campochiaro (The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) and team first confirmed upregulation of VE-PTP expression by hypoxia in endothelial cells in vivo, particularly in ischaemia-driven retinal neovascularisation.

But blocking this protein, which they did in two ways, enhanced TIE2 activation and suppressed neovascularisation.

The first of the two methods was intraocular injection of anti–VE-PTP antibody, which has previously been shown to result in TIE2 activation, in mouse models of retinal and subretinal neovascularisation. An injection of 2 µg significantly reduced the area of retinal neovascularisation in eyes compared with doses of 0.1 µg or 0.5 µg and versus immunoglobulin G as a control.

The second was systemic or intraocular injection of AKB-9778, a potent and selective inhibitor of VE-PTP catalytic activity, which in cultured endothelial cells stimulated phosphorylation of TIE2 and downstream components of the TIE2 signalling pathway.

The researchers note that this TIE2 activation occurred in the absence of angiopoietin (ANG)1 and was enhanced in the presence of ANG1 and ANG2.

AKB-9778 also promoted TIE2 phosphorylation and strongly suppressed neovascularisation in mouse models of neovascular AMD. And was still able to significantly suppress neovascularisation in mice with oxygen-induced ischaemic retinal neovascularisation that was accentuated by the induction of ANG2.

“This finding has important implications, because in disease states complicated by [neovascular] or excessive vascular leakage, such as ischemic retinopathies, ANG2 levels are high and ANG1 levels are low”, the researchers explain in The Journal of Clinical Investigation.

They note that while ANG1-induced TIE2 signalling was blunted by hypoxia, AKB-9778 was unaffected, supporting its use as a therapeutic agent in ischaemic ocular diseases.

Other benefits of AKB-9778 demonstrated in animal models included blocking VEGF-induced leakage from dermal and retinal vessels and suppressing histamine-induced permeability and preventing exudative retinal detachment in double-transgenic mice with high VEGF expression in photoreceptors. It was also found to have no effect on retinal vascular development.

“These data support targeting VE-PTP to stabilize retinal and choroidal blood vessels and suggest that this strategy has potential for patients with a wide variety of retinal and choroidal vascular diseases”, Campochiaro et al conclude.

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