Intravitreal COMP-Ang1 reduces vascular area in advanced diabetic retinopathy.

Abstract

Purpose : Development of new therapeutic targets for halting or slowing the progression of diabetic retinopathy (DR) is critical for treating this dangerous and blinding diabetic complication. We previously showed that early, preventative administration of AAV2.COMP-Ang1 (a bioengineered Angiopoietin1 variant), reduced capillary dropout and retinal vascular permeability in type1 diabetic Ins2^Akita mice. Here we evaluate the therapeutic efficacy of AAV2.COMP-Ang1 treatment on vascular changes in aged mice when administered at 6 months, following the initial development of DR.

Methods : AAV2.COMP-Ang1 carrying a 3’ flag tag was bilaterally injected into the vitreous of male 6-month old Ins2^Akita eyes. Age-matched controls consisted of uninjected C57Bl6 males and of Ins2.^Akita males injected with AAV2.LacZ, AAV2.GFP, PBS or nothing. Mice were sacrificed and their retinas were harvested at 11 months. Anti-flag antibody confirmed COMP-Ang1 expression in flat mount retinas of AAV2.COMP-Ang1 injected animals, while GS1-B4 lectin was used to label vasculature in all retinas. 20x confocal images of the deep and superficial vascular beds were taken on opposite sides of the retinal periphery and vascular densities were measured using AngioTool and averaged for each eye.

Results : The density of deep retinal microvasculature has been previously shown to increase in Ins2^Akita mice compared to wild type mice at 6 months. We found that in 11-month old retinas treated with intravitreal AAV2.COMP-Ang1, superficial and deep vascular areas were both similar to those of age matched wild-type mice (superficial area: WT =17.5%, Akita^Comp-Ang1 = 17.7% n=10, p =0.85; deep area: WT = 30.6%, Akita^Comp-Ang1 = 30.5%, n=10, p=0.9) but were significantly less than vascular areas of Ins2^Akita control retinas (superficial: Akita^control = 20.1%, n = 10, p = 0.01; deep: Akita^control = 33.5%, n=10, p=0.027).

Conclusions : Superficial and deep microvasculature of Ins2^Akita mice shows late changes in vasculature consistent with proliferation, likely due to an increase in retinal hypoxia. Here we show that intravitreally injected AAV2.COMP-Ang1 is effective at halting this increase in both vascular beds, even when administered subsequent to the development of the first detectable vascular defects in Ins2^Akita retinas. This effect is consistent with reduction of retinal hypoxia and improvement in vascular stabilization.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.