Neuro-protection and neuro-regeneration of the optic nerve: recent advances and future directions

Abstract

Purpose of review: Optic neuropathies refer to a collection of diseases in which retinal ganglion cells (RGCs), the specialized neuron of the retina whose axons make up the optic nerve, are selectively damaged. Blindness secondary to optic neuropathies is irreversible as RGCs do not have the capacity for self-renewal and have a limited capacity for self-repair. Numerous strategies are being developed to either prevent further RGC degeneration or replace the cells that have degenerated. In this review, we aim to discuss known limitations to regeneration in central nervous system (CNS), followed by a discussion of previous, current, and future strategies for optic nerve neuroprotection as well as approaches for neuro-regeneration, with an emphasis on developments in the past two years.

Recent findings: Neuro-regeneration in the CNS is limited by both intrinsic and extrinsic factors. Environmental barriers to axon regeneration can be divided into two major categories: failure to clear myelin and formation of glial scar. Although inflammatory scars block axon growth past the site of injury, inflammation also provides important signals that activate reparative and regenerative pathways in RGCs. Neuroprotection with neurotrophins as monotherapy is not effective at preventing RGC degeneration likely secondary to rapid clearance of growth factors. Novel approaches involve exploiting different technologies to provide sustained delivery of neurotrophins. Other approaches include application of anti-apoptosis molecules and anti-axon retraction molecules. Although stem cells are becoming a viable option for generating RGCs for cell-replacement-based strategies, there are still many critical barriers to overcome before they can be used in clinical practice. Adjuvant treatments, such as application of electrical fields, scaffolds, and magnetic field stimulation, may be useful in helping transplanted RGCs extend axons in the proper orientation and assist with new synapse formation.

Summary: Different optic neuropathies will benefit from neuro-protective versus neuro-regenerative approaches. Developing clinically effective treatments for optic nerve disease will require a collaborative approach that not only employs neurotrophic factors but also incorporates signals that promote axonogenesis, direct axon growth towards intended targets, and promote appropriate synaptogenesis.

Figure 1:. Barriers to Optic Nerve Regeneration

Both cell intrinsic and cell extrinsic factors limit the capacity of retinal ganglion cells (RGCs) to regenerate the optic nerve. The mature retina does not retain a reserve of progenitor cells that can replace lost RGCs. Attempts at RGC transplantation are limited by poor integration rates into the native retina. Axonogenesis of injured and transplanted RGCs is limited intrinsically by anti-regenerative transcription factors and extrinsically by glial scar, and myelin by products. Of the RGCs that manage to sprout new axons, they are not myelinated and have been observed to grow towards aberrant targets or overshoot their targets. Upon reaching the diencephalon, regenerated axons form weak synapses with their synaptic partners.