Towards A Microbead Occlusion Model of Glaucoma for a Non-Human Primate

Abstract

Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease causes vision loss through the degeneration of retinal ganglion cell neurons and their axons in the optic nerve. Using an inducible model of glaucoma, we elevated IOP in the squirrel monkey ( Saimiri boliviensis ) using intracameral injection of 35 μm polystyrene microbeads and measured common pathogenic outcomes in the optic projection. A 42% elevation in IOP over 28 weeks reduced anterograde transport of fluorescently-labeled cholera toxin beta from retina to the lateral geniculate nucleus (60% decrease), and to the superior colliculus (49% decrease). Pressure also reduced survival of ganglion cellaxons in the optic nerve by 22%. The same elevation caused upregulation of proteins associated with glaucomatous neurodegeneration in the retina and optic nerve, including complement 1q, interleukin 6, and brain-derived neurotrophic factor. That axon degeneration in the nerve lagged deficits in anterograde transport is consistent with progression in rodent models, while the observed protein changes also occur in tissue from human glaucoma patients. Thus, microbead occlusion in a non-human primate with a visual system similar to our own represents an attractive model to investigate neurodegenerative mechanisms and therapeutic interventions for glaucoma.

Of Mice and Monkeys: Neuroprotective Efficacy of the p38 Inhibitor BIRB 796 Depends on Model Duration in Experimental Glaucoma

“…To examine RGC anterograde transport in SMs, we injected CTB-488 into left vitreous chambers and CTB-594 into right vitreous chambers ( Fig. 1b) and quantified CTB transport to the lateral geniculate nucleus (LGN), the primary ganglion cell subcortical target in primates as previously described 39 . We verified RGC uptake and initial transport of CTB in whole-mounted retinas from vehicle-treated and BIRB 796-treated SMs (Fig.…”

“…We measured intraocular pressure (IOP) bilaterally in awake rats (n = 9 per group) and in anesthetized (2.5% isoflurane) DBA/2 J mice (n = 20 per group) using a Tono-Pen XL rebound tonometer (Medtronic Solan, Jacksonville, FL) as previously described 17,24 . We measured IOP bilaterally in awake SMs (n = 4 eyes per group) using a Tono-Pen XL, a restraint tube, and positive-reinforcement training techniques as previously described 39 . We performed IOP measurements 2-3 times weekly in rodents and weekly in SMs following administration of 0.5% proparacaine hydrochloride ophthalmic solution (Patterson Veterinary Supply, Inc.) as a local anesthetic.…”

“…Here we assessed the neuroprotective effects of BIRB 796 in three species using two models of glaucoma, the DBA/2 J mouse-an inbred strain tending towards IOP elevation with age -and the inducible microbead occlusion model in rat and squirrel monkey (SM) eyes [37][38][39] . The use of different species and approaches to elevate IOP in this study was deliberate, as promising neuroprotective drugs should be tested in multiple animal models to "increase the likelihood of translation to large human clinical trials" 16,40 .…”

The primate model for understanding and restoring vision

“…NHPs have also been used for modeling and developing treatments for complex diseases such as diabetic retinopathy, choroidal neovascularization, wet AMD (47,48), and glaucoma (49,50). Since neovascularization is a common symptom in several ocular diseases, including diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity, an NHP model presenting this feature was created using intraocular administration of adeno-associated virus (AAV) AAV2 vectors encoding human vascular endothelial growth factor (VEGF) (47).…”

“…One of the tissues that contribute significantly to this complex regulation is the trabecular meshwork, which is fully developed only in humans and NHPs (51). Laser-and beadinduced ocular hypertension models in NHPs have been proposed to test and develop treatments for glaucoma (49,50). These models are similar to the human disease, presenting with reduced outflow facility, nerve fiber layer defects, and progressive enlargement of the cup-to-disk ratio, and, thus, they are highly predictive for drug efficacy in humans.…”