Addressing neurodegeneration in glaucoma: Mechanisms, challenges, and treatments.

Glaucoma is the leading cause of irreversible blindness globally. The disease causes vision loss due to neurodegeneration of the retinal ganglion cell (RGC) projection to the brain through the optic nerve. Glaucoma is associated with sensitivity to intraocular pressure (IOP). Thus, mainstay treatments seek to manage IOP, though many patients continue to lose vision. To address neurodegeneration directly, numerous preclinical studies seek to develop protective or reparative therapies that act independently of IOP. These include growth factors, compounds targeting metabolism, anti-inflammatory and antioxidant agents, and neuromodulators. Despite success in experimental models, many of these approaches fail to translate into clinical benefits. Several factors contribute to this challenge. Firstly, the anatomic structure of the optic nerve head differs between rodents, nonhuman primates, and humans. Additionally, animal models do not replicate the complex glaucoma pathophysiology in humans. Therefore, to enhance the success of translating these findings, we propose two approaches. First, thorough evaluation of experimental targets in multiple animal models, including nonhuman primates, should precede clinical trials. Second, we advocate for combination therapy, which involves using multiple agents simultaneously, especially in the early and potentially reversible stages of the disease. These strategies aim to increase the chances of successful neuroprotective treatment for glaucoma.