Characterization of DL-2-aminoadipic acid-induced retinal neovascularization and leakage in nonhuman primates

Abstract

Purpose : To characterize retinal vascular changes resulting from intravitreal (IVT) injection of DL-2-aminoadipic acid (DL-AAA) in the African green monkey. The effect of Lucentis and Eylea treatment on the induced retinal vascular leakage was also evaluated to validate the model for screening candidate antineovascular compounds.

Methods : DL-AAA was administered intravitreally at a dose range from 1 mg to 5 mg in adult St. Kitts green monkeys (Chloroebus sabaeus). Ophthalmic examinations including color fundus photography (CFP), fluorescein angiography (FA), fluorescein isothiocyanate (FITC)–dextran angiography, optical coherence tomography (OCT) and vitreous fluorophotometry (VFP) were conducted up to 32 weeks. Lucentis or Eylea were intravitreally injected, respectively in selected eyes when significant retinal vascular leakage was induced.

Results : Intravitreal administration of DL-AAA resulted in retinal vascular leakage, macular edema and epiretinal membrane formation as early as one week post-injection in a dose-dependent manner. The area of edema expanded to the periphery of the retina, in some instances, with mild disruption of retinal structures, reaching a maximal size at approximately week 6. DL-AAA-induced vascular leakage persisted through week 32. Both Lucentis and Eylea treatments attenuated retinal vascular leakage within one week post-administration, suggesting the retinal vascular leakage was likely due to a disruption of the retinal microvascular endothelium rather than death of endothelial cells. The observed leakage immediately prior to Lucentis treatment reoccurred by 8 weeks after Lucentis treatment, corresponding to drug washout.

Conclusions : DL-AAA induced dose-dependent retinal vascular leakage and epiretinal membrane formation following intravitreal administration. The resulting persistent vascular leakage is attenuated by anti-VEGF therapy, but reoccurrs with drug washed out. These results support the application of DL-AAA-induced retinal vascular leakage and macular edema as a primate model for efficacy evaluations of candidate therapeutics targeting retinal vascular leakage.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.