From Regeneration Failure to Functional Restoration: Unlocking the Neuronal-Intrinsic Regenerative Capacity as a...

Optic neuropathy encompasses ocular conditions arising from traumatic or nontraumatic damage to optic nerves, causing permanent visual impairment due to retinal ganglion cell (RGC) loss and disrupted axonal connections. Glaucomatous optic neuropathy represents the most prevalent form, affecting over 70 million individuals worldwide and causing blindness in nearly 4 million people.

Current treatments targeting elevated intraocular pressure can slow disease progression but cannot restore vision once RGC axons are lost, largely due to regeneration failure in surviving RGCs. This regenerative failure stems not merely from the presence of growth-inhibitory extrinsic factors, but crucially from diminished neuronal-intrinsic regenerative capacity in mature RGCs.

This review explores how intrinsic growth barriers and inadequate activation of pro-regenerative genes impede axonal regrowth following injury, and how manipulations of these pathways facilitate axon regeneration and visual recovery in experimental models. Emerging findings suggest that these pro-regenerative molecules capable of modifying the neuronal-intrinsic regenerative capacity of RGCs can also preserve visual function in pre-clinical glaucoma models. Finally, we discuss challenges and future directions for translating these findings into therapies, including gene delivery strategies, remyelination therapeutics, and systems biology-based in silico drug screening approaches aiming to reshape the therapeutic landscape towards regenerative interventions for glaucomatous and other optic neuropathies.