Abstract
Purpose :
Intravitreal (IVT) injection of DL-alpha-aminoadipic acid (DL-α-AAA) has been shown to induce sustained retinal vascular leakage mimicking hyperglycemic damage to the retina observed in diabetic retinopathy (DR) and age-related macular degeneration (AMD) patients. The goal of this study was to characterize this chronic model in New Zealand Red (NZR) rabbits and to investigate the therapeutic effect of aflibercept and triamcinolone acetonide (TA) up to 12-weeks post dose.
Methods :
To induce the chronic RNV model, 19 NZR rabbits were given an IVT injection of 80mM DL-α-AAA in the left eye. The contralateral eye was not injected and served as a control. 4-weeks post-induction, left eyes were treated via IVT injection (50µl) with 2mg of aflibercept (group 1, n=7), 2mg TA (group 2, n=7), or balanced salt solution (BSS, group 3, n=5). End point parameters included: slit-lamp and indirect ophthalmoscopy, tonometry, optical coherence tomography (OCT), and fluorescein angiography (FA). All parameters were assessed at baseline, up to 4-weeks post-induction, and up to 12-weeks post-dose. Following euthanasia, eyes were collected, fixed, sectioned, stained with H&E, and examined by light microscopy.
Results :
As early as 1-week after injection of DL-α-AAA, increase caliper and tortuous retinal vasculature and extensive fluorescein leakage was observed on FA. By 4-weeks post-induction, ophthalmoscopy reveled 74% of injected eyes displayed perivascular retinal edema and OCT scans showed retinal thinning. In BSS treated eyes, this phenotype was chronic and continued for the duration of the study (16-weeks). On FA analysis, inhibition of fluorescein leakage in aflibercept treated eyes was observed for to 10-weeks post-dosing while TA treated eyes inhibited leakage up to 12-weeks. Rabbits experienced a slight increase in intraocular pressure over the course of the study but were within the normal ranges for this species.
Conclusions :
TA treatment demonstrated a longer lasting rescue phenotype compared to a single injection of aflibercept. This was likely due to its enduring suspension formulation and anti-inflammatory effect. This chronic model of retinal neovascularization can be used to provide effective proof of concept of novel test articles or delivery methods that are in development for ischemic retinopathies.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.