Abstract
Purpose :
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerative disorders with at least 60 genetic loci so far. Most RP genes are primarily or exclusively expressed in rod photoreceptors, which mediate low-light vision, eventually resulting in their death. However, as a result of rod death, the cone function and survival decline. This results in an overall decline in the quality of life of patients due to diminished visual acuity, color discrimination, and daytime vision. The non-autonomous death of cones suggests the existence of non-genetic mechanisms that could be shared in cases where rods die due to disparate mutations. Previous work implicates metabolic perturbation and oxidative stress as contributors to cone death. Among metabolic pathways, deficiency of glucose to cones is thought to be a cause with its uptake and/or delivery impeded after rod cell loss. We hypothesized that promoting glucose metabolism in cones may enhance their survival.
Methods :
We developed Adeno-associated virus (AAV) vectors to promote non-native gluconeogenesis in cones with the hypothesis that this approach should bypass problems related to glucose delivery or uptake. We delivered the gluconeogenic AAVs via subretinal delivery in three mouse models of RP that have different mutations in rod-specific genes (Pde6b and Rhodopsin) and undergo cone death with differing kinetics. AAVs encoding the green fluorescent protein (GFP) (AAV-GFP) were coinjected to track the surviving cones. The control group consisted of animals injected solely with AAV-GFP. Cone survival was assessed by direct counts on flat-mounted retina. Visual acuity was assessed by optometry. Gluconeogenesis was also combined with antioxidant therapy relying on Nrf2 overexpression and cone survival was quantified.
Results :
Treated groups, which received the gluconeogenesis genes via AAVs, had prolonged cone survival compared to control groups which received only AAV-GFP. This was accompanied by an improvement in visual acuity with gluconeogenesis at all assayed time points. Combining gluconeogenesis with antioxidant therapy had an additive effect on cone survival.
Conclusions :
Our results indicate that a viral gene delivery approach to promote gluconeogenesis provides a therapeutic option that can be generically employed to enhance cone survival and function in RP.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.