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

Abstract

Purpose : 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. Therefore, we would like to develop a gene-agnostic therapy, aimed at preserving cone photoreceptors and daylight vision, independent of the specific genes that are involved.

Methods : We used adeno-associated virus (AAV) to deliver candidate genes to the eyes of neonatal RP mice. The AAV8 capsid employing cone-specific promoters was used for cell type-specific expression. AAV delivery was via subretinal injections. The initial screen was done in rd1 mice, the fastest RP degeneration strain, followed by infections of the rd10 and rho^-/- strains. Rd1 retinas were harvested at P50, flat-mounted and the surviving cones within the central half of radius were quantified. To test for an effect on visual function, optomotor behavioral assays were used on treated rd10 and rho^-/-mice.

Results : We found that AAV-Txnip prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. The rescue effect of Txnip depends upon lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Moreover, the combination of Txnip.C247S and Nrf2, a therapeutic transcription factor which regulates the oxidative stress response, provides a synergistic effect in rescue.

Conclusions : These and additional observations lead to a model wherein Txnip shifts cones from their normal reliance on glucose, to enhanced utilization of lactate for mitochondrial metabolism, thus benefiting the cones in a condition where the glucose supply is limiting.

This is a 2021 ARVO Annual Meeting abstract.