Keith Martin
Research shows that regeneration of the optic nerve is possible. However, directing axonal growth in a way that will restore cortical function and spatial perception remains an unsolved problem, said Keith Martin MD, FRCOphth, Cambridge University, Cambridge, UK.
“It is a very exciting time for the understanding of the biology of optic nerve degeneration and how to simulate these cells and potentially how to guide the regenerated axons to their targets in the brain,” Dr Martin told the 13th European Glaucoma Society Congress in Florence, Italy.
Dr Martin noted that as far back as 1987, work by Albert Aguayo and associates showed that a transected optic nerve could be successfully connected to the superior colliculus of the brain using a peripheral nerve graft. In animal experiments this approach has resulted in functional axonal connections throughout the visual system and has even restored the subjects’ pupillary reflex (Vidal-Sanz et al.,
J Neurosci. 1987;7:2894-2909).
“The issue is not whether retinal ganglion cells have the capacity to regenerate, but in the normal circumstances they don’t tend to because the environment of the central nervous system is inhibitory,” Dr Martin said.
BLOCKING INHIBITION
The inhibitory factors of neuroregeneration include myelin-associated glycoproteins, chondroitin sulphate proteoglycans and neurite outgrowth inhibitory protein (NOGO). Research has shown that, to a limited extent, these inhibitory factors can be blocked, stimulating retinal ganglion cell regeneration.
Dr Martin reported that he and his associates have conducted optic nerve regeneration experiments using stem cell transplantation enhanced with chondroitinase ABC, an enzyme that breaks down chondroitin sulphate proteoglycans. They found that the implanted stem cells differentiated into Muller stem cells, and that the anti-inhibitory enzyme appeared to facilitate neurite outgrowth from the transplanted Muller stem cells (Bull et al.,
Invest Ophthalmol Vis Sci. 2008; 49:3449-56).
“What we’re working on now is combining intrinsic mechanisms which induce a pro-regenerative response and an extrinsic response which reduces inhibition to regeneration within the optic nerve,” Dr Martin said.
STIMULATING AXON GROWTH
Methods to directly stimulate retinal ganglion cell regeneration that have been demonstrated in animals include damaging the crystalline lens (Lorber et al.,
Eur J Neurosci. 2005 Apr;21(7):2029-34) and also, paradoxically, raising IOP (Lorber et al.,
Neurobiol Dis. 2012, 45:243-252). Ganglion cells from eyes with glaucoma may therefore be more primed to regenerate and the effect of the disease response appears to be modulated by activated glia, he said.
More recently, Craig Pearson MD, PhD, and the team at Cambridge have shown that arylsulfatase B (ARSB) significantly enhances axonal regeneration in vivo when the enzyme is delivered to the injured optic nerves of adult mice in combination with intravitreal injection of zymosan and CPT-cAMP, an intrinsic growth stimulus (Pearson et al.,
eLife. 2018;7:e37139 DOI:10.7554/eLife.37139). ARSB has the advantage of already being FDA-approved for the treatment of lysosomal disorders.
Directing the axonal growth in ways that restore function remains a problem. In knock-out mice that lack the regeneration-inhibiting PTEN/SOCS3 gene, optic nerve damage is followed by robust axonal regeneration. However, the axon growth tends to follow twisted paths through the optic nerve, with many axons reversing course and others extending towards the other eye (Luo et al.,
Exp Neurol. 2013 ; 247: 653–662).
There is also now evidence that axonal growth can be directed more correctly to some extent by combining growth stimulation and/or inhibition-blocking treatments with intensive visual stimulation in one eye and light exclusion, by eyelid suturing or removal, of the other eye. Mice undergoing this regime following optic nerve crush exhibit behavioural responses to light and shadow (Lim et al.,
Nature Neuroscience. 2016; 19:1073–1084).
“The qualifications of that is that so far this has only provided restoration of brainstem level visual functions. But what has not been demonstrated is any restoration of spatial vision, the ability to determine where in a particular space a stimulus is actually located. This is a major challenge at the moment,” Dr Martin said.
Keith Martin: krgm2@cam.ac.uk
