The study by Hu et al. examined the effects of SARM1 inhibition in glaucoma and experimental autoimmune encephalomyelitis mouse models. Rapid loss of nicotinamide adenine dinucleotide (NAD+) has been shown to drive axonal degeneration. Continuous production of NAD+ is thus crucial for axon survival.1 SARM1 (sterile α and TIR motif-containing protein1) possesses NAD+ hydrolase activity, leading to the destruction and lower levels of NAD+, thereby driving axonal loss. Efforts aimed at blocking SARM1 have been demonstrated to be protective in neurodegenerative disease models.2
The authors explored two therapeutic strategies for SARM1 inhibition and compared them with germline SARM1 deletion in three in-vivo optic neuropathy models. These therapeutic approaches included antisense oligonucleotide (ASO) delivery and adeno-associated virus (AAV)-mediated RGC-specific knockdown of SARM1. The authors used a series of approaches to assess therapeutic effects in traumatic optic nerve crush (ONC), silicone oil-induced ocular hypertension (SOHU) glaucoma model, and experimental autoimmune encephalomyelitis (EAE)/optic neuritis model. Their methods included therapeutic impact both structurally (by analyzing number of RGCs, axons and thickness of fiber layers) and functionally through RGC function assessment via electrophysiology.
The study demonstrated that both intravitreal ASO and AAV delivery led to comparable neuroprotective effects on both RGC soma and axons in the SOHU glaucoma model
The study demonstrated that both intravitreal ASO and AAV delivery led to comparable neuroprotective effects on both RGC soma and axons in the SOHU glaucoma model. Strikingly, the effects of these two approaches differed in the ONC model, where a protective effect was observed only in RGC axons and not in RGC soma. Interestingly, neither of the two intravitreal SARM1 inhibition strategies, nor germline SARM1 knockout (KO), had any impact on RGC or ON survival in the EAE/optic neuritis model suggesting distinct mechanism of pathology and reason for RGC loss in this model.
In summary, the authors have shown that SARM1 inhibition is neuroprotective in glaucomatous and traumatic optic neuropathies but not in the condition characterized by the loss of myelination of ON. Furthermore, the study has demonstrated the effectiveness of local inhibition of SARM1 via intravitreal injection of ASO and AAV-mediated RGC-specific knockdown, thereby minimizing the risk of systemic side effects associated with gene modulation.