Abstract
Presentation Description :
Inherited retinal diseases (IRDs) are one of the leading causes of vision loss. They are mainly caused by a loss of the post-mitotic photoreceptor neurons of the retina, or by the degeneration of the retinal pigment epithelium (RPE). Unfortunately, once these cells undergo damage, it is irreversible and leads to permanent vision impairment. We are investigating critical cellular pathways that can promote the resilience of the photoreceptors against cell death and delay vision loss for patients with IRDs. To identify potential pathways, we performed proteomics on retina samples from a mouse model of retinitis pigmentosa (RP). We found that at disease onset, cellular energy and metabolic pathways were disrupted. We then designed an in vivo screen to deliver metabolites prior to disease onset in the RP mouse. Although many metabolites failed to have an effect, we found that alpha-ketoglutarate (α-KG) was able to prolong photoreceptor survival and delay vision loss. We discovered that α-KG acts to enhance tricarboxylic acid (TCA) cycle activity in the neural retina. We further showed that supplementation with two other TCA cycle intermediates are also able to prolong photoreceptor survival and delay vision loss. Excitingly, this beneficial effect was not specific to the causal genetic mutation, as supplementation with each of these three metabolites prolonged visual function in a mouse model of aRP carrying a different gene mutation. Intriguingly, we discovered that this supplementation approach created a “window of resiliency” in both the arRP and adRP mouse models. This “window” reflects a timeframe in which the photoreceptors are resilient against death in the diseased environment, and later, outside of this “window” they lose the resiliency and succumb to cell death. We are using this “window of resiliency” as a novel tool to define the mechanism by which α-KG and succinate supplementation provides this resilience against photoreceptor degeneration during RP disease. Currently, we have found that cellular signaling pathways (sphingosine-1-phosphate, mTOR and HIFα pathways) are implicated as potential mechanisms underlying this photoreceptor resiliency. Further understanding of the balance between photoreceptor metabolism and its dysregulation during disease has broad implications for patients with RP and other forms of retinal degenerative disease.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.