Primate model of chronic retinal neovascularization and vascular leakage

• Published in: Experimental eye research Vol. 195; p. 108031
• Main Authors: Patel, Chintan, Goody, Robin, Hu, Wenzheng, Kurian, Anish, James, Donnicia, Torres, Richard, Christie, Lori-Ann, Hohman, Thomas, Lawrence, Matthew
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2020
• Subjects: Animals; Chlorocebus aethiops; Chronic Disease; Disease Models, Animal; Female; Fluorescein Angiography - methods; Fundus Oculi; Male; Retinal Neovascularization - diagnosis; Retinal Vessels - pathology; Tomography, Optical Coherence - methods
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2020.108031

The purpose of this study was to characterize and develop a primate model of chronic retinal neovascularization and vascular leakage that can be employed to assess efficacy of experimental therapeutics targeting retinal ischemic and neovascular diseases. African green monkeys received bilateral intravitreal (IVT) injection of DL-alpha-aminoadipic acid (DLAAA; 5 mg) following ophthalmic examination, color fundus photography, fluorescein angiography (FA) and optical coherence tomography (OCT). Imaging was repeated to evaluate progression and subsequent stabilization of retinal vascular pathology elicited by DLAAA. Aflibercept (Eylea) was administered IVT (1.4 mg) to assess effects on vascular leakage. Ocular tissue was collected for histopathology and glial fibrillary acidic protein (GFAP), von Willebrand Factor (vWF), CD105/endoglin, VEGF and CD68 immunohistochemistry to study retinal degeneration and vascular remodeling. IVT DLAAA administration resulted in telangiectatic vessel formation as early as two-weeks post-injection, followed by retinal vascular leakage and inner retinal edema. Neovascular lesion progression was evident up to 8–10 weeks post-injection before stabilizing into a vascular leakage state that persisted beyond 90 weeks. Histopathology and immunostaining revealed retinal degeneration and neovascularization, increased expression of vWF, CD105/endoglin, VEGF and CD68 immunoreactivities in addition to Müller cell loss. Aflibercept significantly attenuated vascular leakage for 2–4 weeks before progressive return of leakage from weeks 4–8. Lesions remained responsive to anti-VEGF administration at 90 weeks after DLAAA injection. Findings support application of the primate DLAAA-induced retinal vascular leakage model for efficacy evaluations of candidate therapeutics and sustained release strategies targeting exudative AMD, diabetic retinopathy, macular telangiectasia and other retinal ischemic and neovascular diseases. Findings confirm relevance of the DLAAA primate phenotype to understanding shared retinal vascular disease mechanisms and macular susceptibility to vascular and metabolic insults.
•DL-2-aminoadipic acid (DLAAA) induces chronic retinal vascular leakage in primates.•DLAAA induces retinal neovascularization and edema, followed by atrophy.•Vascular leakage responds to anti-VEGF therapy before returning after drug washout.•DLAAA model enables evaluation of retinal neovascular therapeutic candidates.