Comparison of Glaucoma-Relevant Transcriptomic Datasets Identifies Novel Drug Targets for Retinal Ganglion Cell Neuroprotection.

Tim J Enz,Pete A Williams,James R Tribble

doi:10.3390/jcm10173938

Tim J Enz, Pete A Williams + Show 1 more

Open Access

https://doi.org/10.3390/jcm10173938

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Abstract

Glaucoma is a leading cause of blindness and is characterized by the progressive dysfunction and irreversible death of retinal ganglion cells. We aimed to identify shared differentially expressed genes (DE genes) between different glaucoma relevant models of retinal ganglion cell injury using existing RNA-sequencing data, thereby discovering targets for neuroprotective therapies. A comparison of DE genes from publicly available transcriptomic datasets identified 12 shared DE genes. The Comparative Toxicogenomics Database (CTD) was screened for compounds targeting a significant proportion of the identified DE genes. Forty compounds were identified in the CTD that interact with >50% of these shared DE genes. We next validated this approach by testing select compounds for an effect on retinal ganglion cell survival using a mouse retinal explant model. Folic acid, genistein, SB-431542, valproic acid, and WY-14643 (pirinixic acid) were tested. Folic acid, valproic acid, and WY-14643 demonstrated significant protection against retinal ganglion cell death in this model. The increasing prevalence of open access-omics data presents a resource to discover targets for future therapeutic investigation.

Highlights

Glaucoma is a common neurodegenerative disease characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs), the major output neurons of the retina
The shared DE gene list common to all three models was queried in the Comparative Toxicogenomics Database (CTD), which compiles known gene/protein interactions with chemicals based on published data, and compounds targeting a significant proportion of the identified DE genes (>50% occurrence) were identified
Glaucoma is a complex neurodegenerative disease in which the only shared and clinically defined feature is the progressive dysfunction and degeneration of RGCs

Summary

Introduction

Glaucoma is a common neurodegenerative disease characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs), the major output neurons of the retina. The disease clinically manifests with deterioration of visual sensitivity and progressive visual field deficits. The major risk factors for glaucoma are age, genetics, and elevated intraocular pressure (IOP). IOP management remains the only clinically available therapy and, to date, there are no clinically available neuroprotective strategies for glaucoma. Despite continuing attempts to lower IOP pharmacologically and surgically, a significant percentage of patients progress to blindness in one or both eyes [1]. Affecting ~80 million patients worldwide, glaucoma is the most common irreversible blinding disease, constituting a substantial health and economic burden [2]. Efficient neuroprotective therapies would be of great value

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