Neurotrophic factor delivery as a protective treatment for glaucoma

https://doi.org/10.1016/j.exer.2010.05.016Get rights and content

Abstract

Glaucoma is a progressive optic neuropathy and a major cause of visual impairment worldwide. Neuroprotective therapies for glaucoma aim to ameliorate retinal ganglion cell degeneration through direct or indirect action on these neurons. Neurotrophic factor (NTF) delivery is a key target for the development of potential neuroprotective glaucoma treatments. This article will critically summarize the evidence that NTF deprivation and/or dysfunction plays a role in the pathogenesis of glaucoma. Experimental support for the neuroprotective potential of NTF supplementation in animal models of glaucoma will be reviewed, in particular for brain-derived neurotrophic factor, ciliary neurotrophic factor, and glial cell line-derived neurotrophic factor. Finally, the challenges of clinical translation will be considered with an emphasis on the most promising NTF delivery strategies including slow-release drug delivery, gene therapy, and cell transplantation.

Introduction

Glaucoma is an age-related optic neuropathy characterized by the loss of retinal ganglion cells (RGCs), excavation of the optic disc, and progressive visual field loss. An ageing population and sub-optimal therapies results in this disease ranking as the leading cause of irreversible blindness in the world (Quigley and Broman, 2006). Current pharmalogical and surgical glaucoma treatments act by reducing intraocular pressure (IOP), the most important risk factor for the onset and progression of the condition. However, some glaucoma patients continue to lose vision rapidly due to uncontrollable IOP or even despite reasonable therapeutic IOP control. Therefore, novel adjunctive glaucoma treatments capable of halting RGC death and functional loss are urgently required.

Neuroprotective strategies for glaucoma aim to prevent optic nerve degeneration through direct or indirect action on RGCs. Here we review the potential of neurotrophic factor (NTF) delivery strategies for clinical translation in glaucoma therapy. We begin by identifying key mechanisms and examining the role that NTF deprivation and dysfunction plays in glaucomatous pathophysiology. We then evaluate the efficacy of attempts to confer NTF-mediated neuroprotection in experimental glaucoma models via direct application, slow-release devices, gene therapy, and cell transplantation. In addition, the obstacles to clinical translation are addressed.

Section snippets

Neurotrophic factor signaling pathways and expression patterns

NTFs are small, secreted proteins that play important roles in the development and maintenance of the nervous system. While numerous NTFs are expressed throughout the central and peripheral nervous systems, those most applicable to glaucoma primarily belong to the nerve growth factor (NGF) and the 130 kDa glycoprotein (GP130) cytokine families. In addition, a strong neuroprotective role for glial cell line-derived neurotrophic factor (GDNF) has been suggested. Simplified signaling pathways

Evidence for neurotrophic factor deprivation and dysfunction in glaucoma

Blockade of retrograde axonal transport in RGCs by ocular hypertension (OHT) is thought to contribute to the pathogenesis of glaucoma by triggering apoptosis due to reduced bioavailability of essential survival factors to the retina (Quigley, 1995, Quigley, 1999). Generalized impairments in optic nerve axonal transport were identified in primates following IOP elevation as early as the 1970s (Anderson and Hendrickson, 1974, Quigley and Anderson, 1976, Minckler et al., 1977, Quigley and Addicks,

Neurotrophic factor delivery methods

Given that NTF supply is important for neuronal survival during development and may be impaired in glaucoma, thereby potentially contributing to RGC loss, experimental protective strategies have aimed to supply exogenous NTFs to curb neurodegeneration. It is well documented that NTF supplementation enhances survival of cultured RGCs in vitro, however, here we will focus on the success of such approaches in experimental in vivo models of RGC neurodegeneration. Fortunately, direct access to the

Conclusions

Published evidence suggests that NTF deprivation and dysfunction may play an important role in the pathophysiology of glaucoma. The observations that elevated IOP blocks retrograde transport of BDNF and that delivering BDNF directly to the retina can be neuroprotective support this hypothesis. However, dysregulation of other NTFs, as well as NTF receptors and signaling pathway components in the retina, should not be forgotten. The notion that RGC loss might be attenuated by NTF supplementation

Acknowledgements

TVJ is supported by a National Institutes of Health OxCam Scholarship and the Gates-Cambridge Trust, NDB is supported by Fight for Sight (UK), KRM is supported by a GSK Clinician Scientist Fellowship. This work was supported by Cambridge University Hospitals NHS Foundation Trust, the Jukes Glaucoma Research Fund, and the National Eye Institute Intramural Research Program.

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