Effects of multiple intravitreal anti-VEGF injections in a rabbit model of persistent retinal neovascularization (PRNV)

Abstract

Purpose : Multiple intravitreal injections of anti-VEGF agents that are commonly needed for the treatment of intraocular vascular diseases, however, studies have yet to compare the long-term effectiveness and safety of repeated intravitreal injections with these agents.
The purpose of this study is to develop an experimental model of retinal neovascularization with persistent leakage in rabbits to evaluate the long term effect of the repeated intravitreal injections of the anti-VEGF drugs currently in clinical use.

Methods : Persistent retinal neovascularization (PRNV) was induced by a single intravitreal injection of gliotoxin, DL-α-aminoadipic acid (DL-AAA) in Dutch-Belted rabbits. Pharmacology study was performed after 8 weeks of the PRNV induction with stable PRNV-related fluorescein leakage. Three anti-VEGF agents that currently use in clinical were formatted 30ul, equal to 0.6 times human dose and masked with Drug A, B and C. The 3 agents were administrated by intravitreal injections for 3 times and repeated in every 9 weeks.
The effects of multiple intravitreal anti-VEGF injections was evaluated by non-invasive ocular imaging including fundus Photography, fluorescein angiography (FA) and optical coherence tomography (OCT) and were followed up for a total of 36 weeks. The eyes were collected for histological and immunohistochemical analysis at the endpoint.

Results : DL-AAA injection produced clinical PRNV as revealed by fluorescein angiography (FA) at 8 weeks with retinal disorganization in the visual streak. The hyper-fluorescent leaking lesion increased rapidly in the first 4 weeks, stabilized during 4 to 8 weeks, and was persistent throughout the entire observation of 12 months without regression. Intravitreal administration of the anti-VEGF drugs caused complete inhibition of the hyper-fluorescent leak for about 6 to 8 weeks for the all 3 agents. However, there was a difference in the efficacy between drugs seen after the 3 repeat injections. Drug A demonstrated great reduction of leakage as well regression of total PRNV area compared with the other anti-VEGF agents. It was confirmed by immunohistochemistry indicated the beneficial effects on PRNV regression.

Conclusions : This model provides a unique tool to evaluate novel anti-VEGF formulations and therapies and in particular, to compare their duration of action.

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