Deep Phenotyping of a Spontaneous Nonhuman Primate Model of Diabetic Macular Edema

Abstract

Diabetic retinopathy (DR) is a diabetic complication involving damages to blood vessels in the retina that, if left untreated, can lead to blindness. It is estimated that over 93 million people suffer from DR worldwide and in fact the disease accounts for 12% of all new cases of blindness each year in the United States. Diabetic macular edema (DME) is one of the manifestations of DR, in which fluids leak from the blood vessels into the centre of the macula, causing pain, swelling, and blurred vision. However, the underlying pathogenesis of DR/DME is complex and not well understood, thus impeding the development of effective treatment. Consequently, the use of animal models of DR is of critical importance for better understanding of the underlying pathogenesis of DME, as well as developing new drugs. Non-human primate (NHP) models of diabetes are known to be the most clinically translatable animal models, where the animals develop major clinical phenotypes along the disease progression, including DR. As such, in this study we phenotyped a cohort of type 2 prediabetes/diabetes NHPs (n=123, weight: 11.5±2.0kg, age: 15.5±2.9years) using clinically relevant circulating and imaging biomarkers. Specifically, spectral domain optical coherence tomography (OCT) was first used to identify a subgroup of the animals with significantly thickened retina (329 ± 6.77µm) with an accumulation of hard exudates and inter-retinal cysts (n= 59). Fundus fluorescein angiography (FA) imaging further confirmed the presence of retinal vascular leakage into the cystoid spaces during the late-phase FA. Levels of vascular endothelial growth factor (VEGF) in both plasma and vitreous fluid were also measured and the results appear to correlate with retina thickness (vs. aged-matched controls). Taken together, our findings demonstrate a clinically translatable NHP model for DR/DME that allows characterization of disease progression in vivo, investigation of co-morbidities, and evaluation of novel therapeutics. Disclosure S. Chia: Employee; Self; Merck Sharp & Dohme Corp.. L. Gong: None. S. Tiu: Employee; Self; Merck & Co., Inc. S. Annamalai: Employee; Self; Merck Sharp & Dohme Corp. N.X. Li: Employee; Self; Merck & Co., Inc.. L. Pan: None. L. Hong: Employee; Self; Merck Sharp & Dohme Corp.. Employee; Spouse/Partner; Illumina, Inc. A. Abu Bakar Ali: Employee; Self; Merck & Co., Inc. C. Chin: Employee; Self; Merck & Co., Inc.. W. Zeng: None.