Abstract
Purpose :
Characterize pathological vessel morphology and retinal edema induced by intravitreal (IVT) DLAAA in the St. Kitts African green monkey (Chlorocebus sabaeus).
Methods :
Animals (n=12) deemed healthy by prescreen ocular exam received an IVT injection of 3.75mg (n=6) or 5mg (n=6) of DLAAA; eyes that failed to develop vascular pathology determined by fluorescein angiography (FA) received a second injection 2 wks later. All animals received slit lamp exam, color fundus imaging, FA, optical coherence tomography (OCT), and OCT angiography (OCTA) at baseline, and at 6, 8 and 10wks post-DLAAA. At week 10, 16 eyes (10 animals) balanced based on leak area at 8 wks, received vehicle (n=8) or 1.25mg of Avastin (n=8), and were followed for 9 additional weeks. Neovascular leak was quantified using Photoshop. OCT scans were segmented with Orion and OCTA images registered with Photoshop.
Results :
Consistent with our prior findings, within 2wks, IVT DLAAA resulted in dose-dependent retinal degeneration in the macular region. OCTA imaging revealed retinal neovascularization (RNV) in the affected area, which correlated with increased vascular permeability. Sustained macular edema developed in eyes that received 3.75mg, but not 5mg, of DLAAA, despite more extensive retinal degeneration in the latter. Avastin led to a decrease in foveal subfield thickness within 10 days of treatment in eyes that developed macular edema, as well as a reduction in vascular leak area, with a maximal effect of 66±29% (mean±SD; p=0.004) observed 3wks post-treatment, concomitant with narrowing and regression of the neovascular lesions. No significant changes were observed in vehicle-treated, DLAAA-diseased eyes.
Conclusions :
The nonhuman primate DLAAA model recapitulates multiple aspects of human disease such as persistence and stability of RNV lesions, and, importantly, sensitivity to VEGF blockade. The dose-dependent disease phenotypes we identified and quantified – wherein a lower DLAAA dose leads to mild retinal degeneration, small RNV lesions, and macular edema, and a higher dose results in extensive retinal degeneration and RNV – provide unique, translationally-relevant preclinical models for testing the efficacy of novel treatments for RNV disease.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.