Neuroprotective Strategies for the Treatment of Inherited Photoreceptor Degeneration

Abstract

Photoreceptor degeneration is the hallmark of several groups of inherited neurodegenerative diseases causing blindness in humans. These diseases are a major cause of visual handicap and to date no satisfactory treatment is available. Here, we briefly review different approaches for the treatment of photoreceptor degeneration, to then focus on neuroprotection. Up to date, translation of experimental neuroprotection into a clinical setting has faced major obstacles, which are in part due to an incomplete understanding of the regulation of pro-survival as well as neurodegenerative mechanisms. Previous approaches were often based on the hypothesis that photoreceptor cell death was governed by a single, apoptotic cell death mechanism. This perception has turned out too simple as recent work has demonstrated that photoreceptor cell death is governed by non-apoptotic mechanisms as well. Moreover, there is evidence, that several different destructive processes are executed in parallel. Briefly reviewing the complexity of degenerative mechanisms, this review discusses relevant pathways, options to target signaling cascades, final common denominators of cell death, and the interplay of events executing cell death. In particular, we focus on cGMP-signaling, epigenetic and proteolytic processes and the corresponding enzymatic activities that were recently shown to be causally related to retinal degeneration. Finally, we illustrate how a better understanding of destructive mechanisms may enable identification and validation of novel targets for neuroprotection, and allow development of next generation neuroprotective treatments as well as combination therapy.

Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement

“…In other words, there is a need to advance the therapy by taking a step back to proof-of-concept studies in animals at ages that better model the human patients. Among the possibilities to consider for refinement is delivery of agents to prevent the loss of retinal cells, such as neuroprotective, prosurvival, or antiapoptotic factors or antioxidants (66)(67)(68)(69), sequentially or simultaneously with a more advanced version of gene augmentation therapy to increase chromophore to the remaining rod, extrafoveal cone, and foveal cone photoreceptors.…”

How Excessive cGMP Impacts Metabolic Proteins in Retinas at the Onset of Degeneration

“…Intracellular cGMP levels increase 5–10 times higher than normal just before the onset of degeneration. We are investigating the idea that accumulation of cGMP causes metabolic failure in several retinal degeneration models (Trifunovic et al 2012; Arango-Gonzalez et al 2014). To understand the link between cGMP accumulation and photoreceptor degeneration, we used mass spectrometry to quantify changes in protein and protein phosphorylation caused by AIPL1 deficiency.…”

Yttrium oxide nanoparticles prevent photoreceptor death in a light-damage model of retinal degeneration

“…Progressive dysfunction and degeneration of photoreceptors (PR) is a leading cause of blindness [1]. PRs experience high light exposure compared to other parts of the body and also have been shown to experience oxidative stress and accumulation of reactive oxygen species (ROS), processes which are implicated in the pathobiology of many retinal diseases including diabetic retinopathy [2] and age-related macular degeneration (for recent review of this literature, see [3]).…”