Non-human primate laser-induced NAION model for assessing neuro-rejuvenating gene therapies

Abstract

Purpose : NAION (Non-Arteritic Anterior Ischemic Optic Neuropathy), which is the second most common ischemic optic neuropathy in adults, is characterized by acute, monocular, and painless visual loss due to ischemic damage at the optic nerve head. The resulting largely nonreversable vision loss has no treatment and there is a 25% lifetime risk of involvement of the fellow eye. Notably, the pathophysiology is not completely understood. As a result, animal models are needed to advance understanding of NAION and to assess emerging treatments. Existing rodent NAION models are not ideal due to differences between rodent and human visual systems. Bernstein et al first developed and tested a laser induced Non-Human Primate (NHP) NAION model. The current study examined the variability in functional and histological damage to determine its utility in evaluating novel therapies.

Methods : Wild caught African green monkeys (n=8) of comparable ocular health had NAION induced on Day 0 in OS eye: IV rose Bengal (2.5 mg/kg; 0.1 ml/kg of 25 mg/ml) was administered intravenously, then 534 nm laser applied with contact lens at 100mW for 6 seconds to 500 μm spots in each ONH quadrant. OS and OD eyes were evaluated at baseline (Day -21) and weekly until study end point (Day 35) with slit lamp, fundus photography, pERG and VEP(VERIS), cSLO, and OCT (Heidelberg Spectralis HRA with HEYEX). At endpoint, eyes were enucleated and optic nerve sections stained with PPD for axon quantification; 8 mm punches of the whole mounted retinas were collected for IHC.

Results : Laser induced NAION triggered significant RNFL swelling on OCT at the ONH by Day 7 as compared to baseline. The lowest pERG responses (absolute N95 amplitude; V 10^-6) compared to baseline were on Day 42 (6.9 ±1.2 vs 2.6 ±0.33 V 10^-6, P=0.0033, n=8). The macular retinal ganglion cell thickness was also reduced on Day 35 as compared to baseline (228.0 ±33.0 vs 354.1 ±7.0μm, P=0.0008) and untreated eyes (228.0 ±33.0 vs 348.8 ±7.0μm, P=0.027) which coincided with a significant reduction in the number of healthy axons in the optic nerve and reduction in macular RNFL thickness.

Conclusions : NHP laser induced ONH damage is a robust and reproducible model of NAION. Inter- and intra-subject variability of functional and histological measurements achieved statistical significance using a reasonable sample size, demonstrating the model’s utility in studies evaluating novel therapies.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.