**1. 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). Despite extensive research, 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 ultimately 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]. Thus, efficient neuroprotective therapies would be of great value.

The underlying mechanisms of RGC degeneration that lead to glaucomatous optic neuropathy have been studied broadly using a number of animal-based models, of which controlled optic nerve crush [3] or transection [4], bead models of ocular hypertension [5,6], and the DBA/2J mouse model of glaucoma [7] have been commonly used. Although these models vary in their pathology and mechanism of neural insult, some intrinsic cellular degenerative mechanisms and genetic pathways might be inherent to glaucomatous RGC death. Such mechanisms and genetic pathways would be of particular value as targets for therapeutic interventions.

Recently, RNA-sequencing has been utilized to investigate the molecular mechanisms that drive RGC death in these models, allowing for the identification of differentially

**Citation:** Enz, T.J.; Tribble, J.R.; Williams, P.A. Comparison of Glaucoma-Relevant Transcriptomic Datasets Identifies Novel Drug Targets for Retinal Ganglion Cell Neuroprotection. *J. Clin. Med.* **2021**, *10*, 3938. https://doi.org/10.3390/ jcm10173938

Academic Editors: Miriam Kolko and Brent Siesky

Received: 24 June 2021 Accepted: 27 August 2021 Published: 31 August 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

expressed genes (DE genes) and pathways. Comparing these across models could provide important data for the discovery of common cellular mechanisms and new insights into the pathophysiology of glaucoma. The identified molecules might be targeted by novel or pre-existing pharmaceutical compounds, which would represent a new data-driven approach to discovering potential glaucoma therapeutics, especially when combined with models that allow for rapid testing of drug candidates.

In this study, we identify compounds that could act on altered genes/proteins common to RGC insult using publicly available transcriptomic datasets and validate these using the mouse retinal explant model of RGC degeneration.
