Neuroprotective Strategies for Retinal Ganglion Cell Degeneration: Current Status and Challenges Ahead

Abstract

The retinal ganglion cells (RGCs) are the output cells of the retina into the brain. In mammals, these cells are not able to regenerate their axons after optic nerve injury, leaving the patients with optic neuropathies with permanent visual loss. An effective RGCs-directed therapy could provide a beneficial effect to prevent the progression of the disease. Axonal injury leads to the functional loss of RGCs and subsequently induces neuronal death, and axonal regeneration would be essential to restore the neuronal connectivity, and to reestablish the function of the visual system. The manipulation of several intrinsic and extrinsic factors has been proposed in order to stimulate axonal regeneration and functional repairing of axonal connections in the visual pathway. However, there is a missing point in the process since, until now, there is no therapeutic strategy directed to promote axonal regeneration of RGCs as a therapeutic approach for optic neuropathies.

Targeting Diet and Exercise for Neuroprotection and Neurorecovery in Glaucoma

“…Furthermore, mice carrying a heterozygous deletion of the BDNF gene were not protected by exercise. Other neurotrophins, including neurotrophic growth factor (NGF) and insulin-like growth factor-1 (IGF-1), have demonstrated neuroprotective effects on retinal ganglion cells [ 32 , 33 ]. However, their roles in exercise-mediated protection are less established.…”

Protect, Repair, and Regenerate: Towards Restoring Vision in Glaucoma

“…Animal studies involving either induced (e.g., microbead occlusion, [10]) or genetic (e.g., DBA/2J and GC-1 −/− mice [10][11][12]) elevations in IOP have proven invaluable in identifying key molecular events in RGC dysfunction, which highlight an early window of neuroprotective opportunity. Ideally, neuroprotective strategies should prevent RGC dysfunction and thus subsequent degeneration while promoting repair or even regeneration of damaged tissue to restore vision, as reviewed elsewhere [13]. While clinical neuroprotective trials have proven difficult [14], therapies involving growth factors may have the potential to achieve those goals.…”

Mutation-Independent Therapies for Retinal Diseases: Focus on Gene-Based Approaches

“…Despite the known role of VEGF in neovascularization (Folk and Stone, 2010), it has been shown that VEGF treatment reduces apoptosis in models of glaucoma whereas anti-VEGF therapies exacerbate neuronal cell death (Boia et al, 2020). Engineered zinc finger proteins (ZFPs) that upregulate multiple forms of VEGF in their natural, endogenous, ratios were generated to avoid vascular permeability, edema, and inflammation due to VEGF overexpression.…”

“…Neurotrophic agents have also been tested in ONs ( Boia et al, 2020 ; Figure 2 ). AAV-mediated delivery of Fibroblast growth factor-2, or delivery of the BDNF gene leads to significant increase in RGC survival and reduced RGC axons loss after optic nerve injury or induction of intraocular pressure (IOP) ( Martin et al, 2003 ; Sapieha et al, 2006 ).…”