Epigenetic reprogramming- A novel gene therapy that restores vision loss in a nonhuman primate model of NAION

Abstract

Purpose : We previously published that AAV2 induced transient expression of three reprogramming genes (OSK: Oct4, Sox2, Klf4) in retinal ganglion cells (RGCs) reversed retinal aging and restored lost visual function in old mice and mice with microbead-induced glaucoma. However, in contrast to humans, mice have low visual acuity, non-foveal vision, distinct retinal aging, and they lack higher-order visual processing. As such, non-human primates (NHP) are the gold standard to test the efficacy of a potential gene therapy to restore vision. This study determined whether epigenetic reprogramming restores visual function in a NHP model of NAION (Non-arteritic Anterior Ischemic Optic Neuropathy).

Methods : Prescreened African green monkeys (n=20) had NAION induced on Day 0 by iv rose bengal, then lasering the OS eye optic nerve head. Pre-treated NHP on Day -21 received an OS intravitreal (IVT) injection of dox-inducible AAV2-OSK (5.7 x 10¹¹ vg/eye; 1:1 ratio AAV2-TRE-OSK + AAV2-CMV-rtTAV16) (n=6), or vehicle (n=4). Post-treated NHP on Day +1 received an OS IVT injection of AAV2-OSK (n=6), or vehicle (n=4). Daily oral doxycycline was given until end point. Both eyes were examined at baseline and weekly intervals until Day +35 via slit lamp, fundus photography, pERG, VEP, cSLO, and OCT. At the endpoint, eyes were enucleated, optic nerve axons quantitated and retinal whole mounts stained to quantitate RGCs and Klf4.

Results : Consistent with NAION in humans, laser induced NAION damage significantly reduced pERG, OCT measured RNFL thickness, and optic nerve axons when compared to baseline and untreated OD eyes (data in companion abstract). Pre-treated AAV2-OSK eyes displayed significantly elevated pERG responses (absolute N95 amplitude; V 10^-6) as compared to vehicle treated eyes at the endpoint (4.4 ±0.67 vs 2.6 ±0.33 V 10^-6, P=0.025, Day 35). After AAV2-OSK injection, it takes at least one week for OSK expression in RGCs. Post-treated eyes (treated after NAION induction) showed a decline of pERG amplitude equivalent to controls at Day 7. Treated eyes showed a significant recovery by the endpoint (3.8 ±0.29 vs 2.6 ±0.33 V 10^-6, P=0.021, Day 35).

Conclusions : Partial epigenetic reprogramming by AAV2-OSK gene therapy restored parameters of visual pathway function in a NHP model of NAION. These data support the clinical translational potential of this gene therapy for treating human optic nerve diseases.

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