Photoreceptor death is the root cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve photoreceptor survival. The biosynthetic requirement of photoreceptors is among the highest in the body, and to meet this demand, photoreceptors maintain their ability to perform aerobic glycolysis. This highly regulated form of glycolysis allows cells to efficiently budget their metabolic needs and may be a critical link between photoreceptor function and survival. Pyruvate kinase muscle isozyme 2 (PKM2) is a key regulator of aerobic glycolysis. In the present study, we characterized the effect of PKM2 deletion on baseline functioning and survival of photoreceptors over time by utilizing a photoreceptor-specific, PKM2 knockout mouse model. We found that upon PKM2 deletion, PKM1 is upregulated in the outer retina and there is increased expression of genes involved in glucose metabolism, which led to chronic degenerative changes in the outer retina of these mice. We also discovered that this metabolic reprogramming provided a survival advantage to photoreceptors in an experimental model of retinal detachment. This study strongly supports the hypothesis that reprogramming metabolism may be a novel therapeutic strategy for photoreceptor neuroprotection during acute stress.The retina has two circulations-retinal, for the inner retinal neurons, and choroidal, which through the retinal pigment epithelium (RPE), feeds the outer retina. Inner retinal neurons are exquisitely sensitive to ischemia, and irreversible inner retinal injury occurs after 2-4 hours of central retinal artery occlusion 1 . On the other hand, the choroidal circulation supplies the outer retina where the photoreceptors are located. Photoreceptors are therefore deprived of oxygen and glucose when they separate from the underlying retinal pigment epithelium, which occurs in retinal detachment. Unlike inner retinal neurons, photoreceptors are able to withstand prolonged periods of oxygen and nutrient deprivation, as demonstrated by numerous clinical studies that show visual gain when the retina is re-apposed to RPE surgically within days to weeks after initial retinal detachment symptoms 2-4 . It is hypothesized that this survival may be largely secondary to the specific metabolic demands and metabolic machinery present in the photoreceptors.Warburg and colleagues first demonstrated that neoplastic cells convert glucose to lactate despite the presence of oxygen, which is known as aerobic glycolysis or the Warburg effect 5 . In these cells, aerobic glycolysis functions to meet the high demand for metabolic energy and biosynthetic intermediates. Interestingly, Warburg noted that the retina was the only non-proliferative tissue that was capable of aerobic glycolysis and further studies showed that this effect is limited to the photoreceptors [5][6][7][8] . It has been hypothesized that the constant turnover of photoreceptor outer segments, with its extremely high metabolic requirements, drives aerobic glycoly...

Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve photoreceptor survival. Similar to cancer cells, photoreceptors maintain pyruvate kinase muscle isoform 2 (PKM2) expression, which is a critical regulator in aerobic glycolysis. Unlike PKM1, which has constitutively high catalytic activity, PKM2 is under complex regulation. Recently, we demonstrated that genetically reprogramming photoreceptor metabolism via PKM2-to-PKM1 substitution is a promising neuroprotective strategy. Here, we explored the neuroprotective effects of pharmacologically activating PKM2 via ML-265, a small molecule activator of PKM2, during acute outer retinal stress. We found that ML-265 increased PKM2 activity in 661 W cells and in vivo in rat eyes without affecting the expression of genes involved in glucose metabolism. ML-265 treatment did, however, alter metabolic intermediates of glucose metabolism and those necessary for biosynthesis in cultured cells. Long-term exposure to ML-265 did not result in decreased photoreceptor function or survival under baseline conditions. Notably, though, ML-265-treatment did reduce entrance into the apoptotic cascade in in vitro and in vivo models of outer retinal stress. These data suggest that reprogramming metabolism via activation of PKM2 is a novel, and promising, therapeutic strategy for photoreceptor neuroprotection.

Purpose To investigate the clinical features and surgical outcomes of rhegmatogenous retinal detachment (RRD) associated with giant retinal tears (GRTs) at a tertiary referral center. Patients and Methods A retrospective, non-consecutive interventional case series of GRT-associated RRDs that underwent primary surgical repair at the University of Michigan W.K. Kellogg Eye Center between January 1, 2011 and July 1, 2020. Clinical characteristics and preoperative, perioperative, and postoperative data were collected. Results Forty-eight eyes of 47 patients with GRT-associated RRDs met inclusion criteria, including those that were children (under 12 years, N=4, 8.3%), associated with a history of trauma (N=20, 41.7%) or with grade C proliferative vitreoretinopathy (PVR-C) (N=7, 14.6%) at baseline. Median age was 46 years (interquartile range (IQR): 29 years, range: 4 to 72 years), median follow-up was 28 months (IQR: 43 months, range: 3–124 months), and 83.3% (N=40) of subjects were male. Primary surgical repair for GRT-associated RRDs included pars plana vitrectomy (PPV) (N=40, 83.3%), scleral buckle (SB) (N=1, 2.1%), or combined PPV/SB (N=7, 14.6%). Surgical approach commonly involved the use of perfluorocarbon liquid (N=43, 90%) and gas tamponade (N=39, 81%). Single surgery anatomic success (SSAS) was 75% (95% CI: 60%, 85%) at 3 months and 65% (95 CI: 47%, 78%) at 2 years. Final anatomic success was achieved in all 48 eyes (100%). Median visual acuity improved from 20/250 preoperatively to 20/60 at final follow-up, with 44% (N=20) of eyes achieving postoperative visual acuity of 20/40 or better. Conclusion In this series from a tertiary referral center, both complex and non-complex GRT-associated RRDs were most commonly managed with PPV alone, perfluorocarbon liquid, and gas tamponade with favorable final anatomic and visual outcomes comparable to other modern GRT series.