A Novel Method to Achieving Neuroregeneration in Glaucoma | April Editor’s Choice

By Vivek Trivedi | Senior Editor

Illustration by: Michelle Shi | Director of Art & Layout

In his 2014 article, “From Degeneration to Regeneration,” Mark Robles-Long highlights a potential stem cell therapy-based treatment to regenerate neurons that were damaged in patients with Multiple Sclerosis. Recently, new developments have been made in the treatment of another neurodegenerative disease: glaucoma. Glaucoma is the second leading cause of blindness worldwide and is characterized by progressive optic nerve and retinal ganglion cell (RGC) degeneration. The disease is generally associated with an increase in intraocular pressure (IOP), but does not necessarily co-occur with it, as normal-tension glaucoma is marked by damage to the optic nerve and progressive vision loss despite normal IOP. Presently, the only effective treatment modalities used by clinicians all involve lowering IOP by various strategies, including medical and surgical intervention.1 Few strides have been made in restoring or even protecting RGCs from further damage.

To date, the transplantation of various types of stem and progenitor cells were considered to be promising tools that could be used as advanced therapies to treat damage to the central nervous system, including the retina and optic nerve.2 These methods have been studied extensively in animal models. However, several obstacles for their usage have been pronounced. Most notably, it is likely that harmful factors such as those that induce retinal neovascularization would be released from transplanted cells, triggering off-target effects that induce new problems. Additionally, it is not known whether host cells will remain responsive to these stem cell derived neuroprotective factors over a period of several months to years. There is also the risk that transplantation of such highly proliferate cells might carry a risk of tumorigenesis.3 These issues must be resolved before clinical testing in humans can begin to take place.

Smedowski et al. propose a solution to these issues by avoiding the use of stem cells altogether.4 Instead, they offer to use Schwann cells (SC) instead, which are the major glial cells in the peripheral nervous system capable of stimulating regeneration in both the peripheral and central nervous systems. This regeneration creates a generation of new axons in addition to the branching of existing ones. After injury to nerve tissue, SC have been found to secrete various trophic factors and adhesion molecules that contribute to the creation of an environment conducive to spontaneous regeneration of axons. In their study, Smedowski and his colleagues transplanted differentiated SCs into a glaucomatous optic nerve neuropathy in rats. They found that SC treatment increased the expression of synaptophysin, a presynaptic vesicle protein, in certain layers of the retina. This increased expression is thought to be associated with faster axonal transport of synaptophysin to newly grown RGC axon projections that create proper synaptic connections with their target. Furthermore, they were able to find evidence that SC therapy induces neuroregeneration and RGC outgrowth both in ex vivo and in vivo conditions.

The induced synaptic plasticity and neuroregeneration of RGCs in the rat model is a promising step forward in the road to stopping or even reversing the neuropathological damage resulting from glaucoma. Because SCs are already mature and differentiated, there is very minimal risk of uncontrolled proliferation, as is the case with stem cells. Predegenerated SCs may be isolated from peripheral nerves and applied as autotransplants. Although much more robust animal and human clinical trials must be performed before this technique can be applied to a clinical setting, there is hope that the neurodegenerative disease commonly recognized as irreversible may one day have a cure.

References:
1. Tian, K., Shibata-Germanos, S., Pahlitzsch, M., & Cordeiro, M. F. (2015). Current perspective of neuroprotection and glaucoma. Clinical Ophthalmology (Auckland, N.Z.), 9, 2109–2118.

2. Chang, E. E., & Goldberg, J. L. (2012). Glaucoma 2.0: Neuroprotection, Neuroregeneration, Neuroenhancement. Ophthalmology, 119(5), 979–986.

3. Levin, L. A., Crowe, M. E., Quigley, H. A., & The Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants. (2017). Neuroprotection for Glaucoma: Requirements for Clinical Translation. Experimental Eye Research, 157, 34–37.

4. Smedowski, A., Liu, X., Pietrucha-Dutczak, M., Matuszek, I., Varjosalo, M., & Lewin-Kowalik, J. (2016). Predegenerated Schwann cells–a novel prospect for cell therapy for glaucoma: neuroprotection, neuroregeneration and neuroplasticity. Scientific Reports, 6, 23187.

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