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

Yunlu Xue,Emma R West,Christin M Hong,Parimal Rana,Constance L Cepko,David M Wu,Sean K Wang,Helian Feng

doi:10.7554/elife.66240

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 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.

Highlights

Retinitis pigmentosa (RP) is one of the most prevalent types of inherited retinal diseases affecting approximately 1 in ~4,000 people (Hartong et al, 2006)
An additional set of associated virus (AAV) vectors were made based upon the initial screen results, as well as other rationales, to total 20 genes tested in all (Figure 1—source data 1)
The vectors were subretinally injected into the eyes of neonatal rd1 mice, in combination with a vector using the human red opsin (RedO) promoter, to express a histone 2B-GFP

Summary

Introduction

Retinitis pigmentosa (RP) is one of the most prevalent types of inherited retinal diseases affecting approximately 1 in ~4,000 people (Hartong et al, 2006). In RP, the rod photoreceptors, which initiate night vision, are primarily affected by the disease genes and degenerate first. The degeneration of cones, the photoreceptors that initiate daylight, color, and high-acuity vision, follows, which greatly impacts the quality of life. One therapy that holds great promise for RP is gene therapy using adeno-associated virus (AAV) (Maguire et al, 2019). This approach has proven successful for a small number of genes affecting a few disease families (Cehajic-Kapetanovic et al, 2020). Due to the number and functional heterogeneity of RP disease genes ( » 100 genes that primarily affect rods, https://sph.uth.edu/retnet/), gene therapy for each RP gene will be logistically and financially difficult. The suggested mechanisms of cone death include oxidative damage (Komeima et al, 2006; Wellard et al, 2005; Xiong et al, 2015), inflammation (Wang et al, 2020; Wang et al, 2019; Zhao et al, 2015), and a shortage of nutrients (AıtAli et al, 2015; Kanow et al, 2017; Punzo et al, 2012; Punzo et al, 2009; Wang et al, 2016)

Objectives

Results

Conclusion