Innovative IOP-Independent Neuroprotection and Neuroregeneration Strategies in the Pipeline for Glaucoma

Abstract

While sustained reduction of intraocular pressure (IOP) has been shown to halt and/or delay the progressive death of retinal ganglion cells (RGCs) in glaucoma, there exists great interest in the development and validation of IOP-independent therapeutic strategies for neuroprotection and/or neuroregeneration. Multiple etiologies for RGC death have been implicated in glaucoma including defective axonal transport, ischemia, excitotoxicity, reactive oxygen species, trophic factor withdrawal, and loss of RGC electrical activity. However, IOP lowering with medical, laser, and surgical therapies is itself neuroprotective, and investigators are seeking to identify agents that are able to confer neuroprotection independent of IOP reduction, as well as providing for regeneration of nonviable RGCs and their axons to restore and/or maintain functional vision. These innovative strategies in the pipeline include investigation of neurotrophic factors, gene therapy, immune system modulation, and novel neuroregeneration pathways. Alongside this new knowledge, enhanced opportunities for discovery of vision preservation and/or restoration therapies must be weighed against the potential disadvantages of perturbing the complex central nervous system environment.

Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions

“…Glaucoma is the leading cause of global irreversible blindness and is generally categorized into two broad categories: open-angle and angle-closure glaucoma [ 1 , 2 , 3 ]. Current treatment strategies for open-angle glaucoma include medical, laser, or incisional methods to lower intraocular pressure (IOP) [ 4 ]. These current methods to lower IOP are proven to slow the progression of glaucoma-mediated damage and are neuroprotective in nature.…”

“…As current available treatments only address IOP, for ischemic and traumatic optic neuropathies, this treatment strategy is unable to address or reverse neuropathic damage [ 2 ]. Therefore, IOP-independent neuroprotective strategies would be beneficial for early stage intervention, potentially preventing disease progression, and reversal [ 4 ]. Retina ganglion cells (RGCs) are an important interventional target as glaucoma is characterized by optic nerve injury and the loss of RGCs [ 6 ].…”

“…Furthermore, aside from glaucoma, RGC death is central to other optic neuropathies, including demyelinating optic neuritis, ischemic optic neuropathy, and hereditary optic neuropathy [ 2 ]. The various etiologies of RGC death include defective axonal transport, ischemia, excitotoxicity, reactive oxygen species, trophic factor withdrawal, and loss of RGC electrical activity [ 4 , 7 , 8 ].…”

“…The underlying objectives of IOP-independent treatment strategies are to ameliorate optic neuropathies by providing an optimal environment for damaged RGCs and potentially regenerate damaged or dead RGCs into healthy functional ones [ 2 , 4 ]. These different strategies belong to three major categories, which include cell therapy, noncellular neuroprotective therapy, and gene delivery-based neuroprotective therapy.…”

Modeling Retinal Ganglion Cell Dysfunction in Optic Neuropathies

“…Neuroprotection in glaucoma and other optic neuropathies is an area of intense investigation in preclinical models [1][2][3][4][5][6][7][8]. Neuroprotective strategies include a large variety of methods (dietary, exercise, environment, pharmacological, molecular, radiation, stem cells, gene therapy) that target specific aspects of neuronal biology or nonspecifically target conditions such as elevated IOP, inflammation, or immune system malfunction that may eventually cause neuronal damage.…”