Development of diabetic retinopathy and age-related macular degeneration in aged and metabolic dysregulated non-human primates

Abstract

Purpose : Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the leading causes of blindness and there are unmet medical needs for effective therapeutics. The non-human primate (NHP) is a potentially reliable translational animal model for novel drug discovery. Therefore, developing NHP models for DR, AMD and other eye diseases will provide translational value to facilitate drug discovery. We conduct this study to identify and characterize DR, AMD and other eye diseases phenotypes in a large cohort of aged and/or high-fat diet (HFD)-induced type 2 diabetic NHPs at Kunming Biomed International (KBI) to support new eye disease drug discovery with substantive translational value.

Methods :
KBI has over 3000 metabolic disease male cynomolgus induced by either HFD feeding or natural aging. Metabolic disease progression was monitored longitudinally by body weight, intravenous glucose tolerance test (IVGTT), blood pressure and clinical chemistry. Diabetic monkeys are identified based on fasting glucose level > 100mg/dL, glucose disposal rate < 1.3% and HbA1c >5%.
All monkeys were anesthetized with IM ketamine (5-10 mg/kg) and xylazine (0.5-1 mg/kg). Refractive error was assessed using auto refractors keratometer; axial length (AL) was measured using Lenstar Biometer; color fundus photograph, auto fluorescein and fluorescein angiograph (FA) was assessed using a fundus camera with FA; retina thickness, retinal edema was assessed using ocular coherence tomography (OCT). Intra ocular pressure (IOP) was measured using a TonoVET.

Results :
As a progress report, total of 573 monkeys have been screened. Early DR was found in 6% of eyes in diabetic monkeys. In aged NHPs, drusen (soft-, hard- and pseudo-drusen), geographic atrophy and wet-AMD was found in 3%, 0.4% and 0.4% of eyes, respectively. Optic neuropathy was found in 0.4% of eyes. IOP was higher than 21 mmHg in 38% of eyes. High myopia (spherical equivalent, SE≥-6.00D), with/out different phenotypes of retinopathy, was found in 27% of eyes.

Conclusions : Variety of eye diseases, DR and AMD in particular, existed in large cohort of diabetic and/or aged cynomolgus in KBI. These monkey eyes with different diseases that manifested with similar pathological characteristics with human patients will be valuable for research to characterize therapeutics and understand the mechanisms.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.