Abstract
Purpose :
Traumatic Optic Neuropathy (TON) is a debilitating consequence of Traumatic Brain Injury (TBI) that can lead to permanent vision loss, with current treatment options remaining largely ineffective. The purpose of this study was to establish a novel TON model that closely mimics human pathology and to explore potential avenues for therapeutic intervention.
Methods :
We developed a new TON model using computational analysis of skull force transmission to accurately simulate clinical conditions of TON. Long-term post-injury outcomes were studied to assess axonal survival. Single-nuclear and spatial transcriptomics provided insights into the molecular changes post-injury, focusing on gliosis and immune response. We then targeted an astrocyte-microglia signaling pathway both genetically and pharmacologically to evaluate its role in neuroprotection and axonal survival. Additionally, we tested a microinvasive surgical technique aimed at reducing local inflammation and promoting axon preservation.
Results :
Our six-month post-injury findings challenge the prevailing assumption that extensive axon regeneration is required for re-establishing significant connections between the eye and brain. The transcriptomic analyses revealed a complex interplay of gliosis and immune infiltration, with disease-associated microglia/macrophage (DAM) signatures concentrated in areas with surviving myelin and axons. Intervention in the glial crosstalk pathway led to neuroprotection, and the microinvasive surgery resulted in a sixfold increase in rescued axons.
Conclusions :
Our study introduces a new TON model that provides an advanced understanding of TON pathology and identifies a promising molecular target for neuroprotection. The microinvasive surgical approach also offers a potential avenue for treatment. These insights not only pave the way for developing effective TON therapies but may also have implications for addressing other neurodegenerative conditions, marking a significant advance in the field of neurotrauma and repair.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.