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.
Highlights
Glaucoma, a multifactorial disease, is the second leading cause of blindness worldwide, affecting an estimated 76.0 million people worldwide by 2020 and increasing to 111.8 million by 2040 [1]
While glaucoma was historically defined as a disease of elevated intraocular pressure (IOP) greater than 21 mm Hg, population-based studies have shown that one-third or more of persons with open angle glaucoma (OAG) have normal levels of IOP [3]. us, the current definition of primary open angle glaucoma (POAG) is no longer contingent on the presence of “elevated IOP” but rather “a progressive, chronic optic neuropathy in adults where IOP and other currently unknown factors contribute to a characteristic acquired atrophy of the optic nerve and loss of retinal ganglion cells (RGCs)” [4]
The Early Manifest Glaucoma Trial (EMGT) reported that the progression risk of early onset open angle glaucoma (OAG) was reduced by 50% with treatment, and the risk of glaucoma progression was decreased by 10% for each mm of Hg of initial IOP reduction [6]
Summary
A multifactorial disease, is the second leading cause of blindness worldwide, affecting an estimated 76.0 million people worldwide by 2020 and increasing to 111.8 million by 2040 [1]. No increased death of RGCs above baseline was observed when animals were treated with TNF-α inhibitors, and/or knockout mice unable to produce TNF-α were studied [35] Based on their experimental results, the investigators concluded that blocking TNF-α signaling or inflammation may be someday proven helpful in treating glaucoma. A more recent study reported that antagonism of the TNF-α signaling pathway delays axotomyinduced RGC loss in a C57Bl/6 mouse model of traumatic neuropathy though the effect was not as favorable as observed with activation of survival pathways by BDNF [36]. The method of T-cell-based vaccination for morphological and functional neuroprotection may be possible since this therapeutic option has been shown to be effective in retarding RGC cell loss in an inbred Lewis and Sprague-Dawley rat model of glaucoma [37]. Exploration of these T-cell-mediated immune response pathways should be equalized with the potential risk(s) of inducing autoimmune disease
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