Neuroprotection of SARM1 Inhibition in Traumatic and Glaucomatous but not in EAE Optic Neuropathies

Abstract

Purpose : SARM1 deletion is neuroprotective in many but not all neurodegenerative disease models. Optic neuropathy is a group of optic nerve (ON) diseases with progressive degeneration of ON and retinal ganglion cells (RGCs). Here we tested the neuroprotection potentials of two gene therapy strategies for SARM1 inhibition, antisense oligonucleotide (ASO) and CRISPR-mediated gene knockdown, comparing with germline SARM1 deletion, in three optic neuropathy mouse models.

Methods : Mice intravitreal injection was used for retina local ASO delivery or AAV-mediated RGC-specific CRISPR SARM1 knockdown. After SARM1 inhibition, three optic neuropathy models, traumatic ON crush (ONC), silicone oil-induced ocular hypertension (SOHU) glaucoma, and experimental autoimmune encephalomyelitis (EAE)/optic neuritis, were generated. To evaluate the neuroprotective effects of these SARM1 inhibition strategies, in vivo spectral-domain optical coherence tomography (OCT) imaging and post-mortem retina and ON histological analysis were used to estimate survival retinal ganglion cells (RGC) and axons; Pattern electroretinogram (PERG) recording was used to analyze RGC function in response to a visual stimulus.

Results : This study reveals that retinal local SARM1 ASO delivery and AAV-mediated RGC-specific CRISPR knockdown of SARM1 achieve similar neuroprotective effects as SARM1 straight KO: SARM1 inhibition only protects ON but not RGC soma after traumatic ONC injury, however, it protects both RGC soma and axons in SOHU glaucoma model. And these two gene therapy strategies of SARM1 inhibition have no neuroprotective effect on RGCs and ONs in the EAE/optic neuritis model.

Conclusions : Our studies suggest that SARM1 inhibition by local ASO delivery or AAV-mediated CRISPR is a promising neuroprotective gene therapy strategy for traumatic and glaucomatous optic neuropathies, but not for demyelinating optic neuritis.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.