AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a disease gene-agnostic therapy, we screened 20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

Augmentation of CD47/SIRPα signaling protects cones in genetic models of retinal degeneration

“…To test if inhibiting phagocytosis during RP might benefit cones, we created an AAV vector (AAV8-RedO-CD47) using the human red opsin promoter to express CD47 on cones ( Figure 2A ). In wild-type mice injected subretinally with a GFP control vector (AAV8-RedO-GFP), which labels both M- and S-type cones ( 8 ), endogenous CD47 could be seen in retinal plexiform layers, as previously described, but not in photoreceptors ( Figure 2B and ref. 22 ).…”

“…Where does CD47 fit in the landscape of emerging treatments for retinal degeneration? In addition to immune dysregulation, cones in RP appear to face a shortage of glucose, as evidenced by greater cone survival with interventions that boost glucose uptake or the use of alternative fuels ( 6 – 8 ). Degenerating cones further experience increased oxidative stress after the death of rods and may be helped by genes or small molecules with antioxidant activity ( 4 , 5 , 36 ).…”

“…However, rod loss is followed by the degeneration of cones, resulting in deterioration of daylight, color, and high-acuity vision. The reasons for secondary cone degeneration in RP remain incompletely understood but likely include increased oxidative stress ( 4 , 5 ), decreased glucose availability ( 6 – 8 ), and immune dysregulation ( 9 , 10 ). Regardless of the exact etiology, an intervention capable of protecting cones in RP independent of the initial genetic lesion would potentially be beneficial for many patients.…”

Early mitochondrial stress and metabolic imbalance lead to photoreceptor cell death in retinal degeneration

“…Significantly lower content of one isoform of PDC kinase (PDK2) and reduced phosphorylation of the PDC E1 alpha subunit in P6 and P10 rd1 retina suggest a faster-working PDC, which can potentially accelerate flux through the TCA cycle. Our data are concordant with previously reported prolonged photoreceptor survival in mouse models of retinal degeneration by increasing glycolysis flux through inhibition of SIRT6 46 or by promoting lactate catabolism as fuel by Txnip administration 47 . We propose that the faster PDC activity, besides being the consequence of higher mitochondrial calcium, could be an adaptive response of mutant photoreceptors by fine tuning TCA cycle in dealing with the stress.…”

“…Photoreceptors have high energy requirements for maintaining their physiological state in dark and light 43 . Like other neurons, glucose provides the primary source of energy in photoreceptors 9,44 , and the stimulation of glucose uptake and/or metabolic intermediates can be neuroprotective in photoreceptor degeneration 39,[45][46][47] . Specialized cristae architecture, low reserve capacity and high OXPHOS of mitochondria 9,44,48 validate their primary role in providing the energy requirements of photoreceptors.…”