The inter-neuronal relationship between rod and cone photoreceptors in human and mouse is such that rod death always leads to cone death; however, loss of cones has no effect on rods. This phenomenon plays an important role in the inherited retinal degenerative disease retinitis pigmentosa, as most disease-causing alleles identified encode for genes that are exclusively expressed in rods. Since cones are essential for human vision, it is their loss that leads to blindness. We have recently proposed that cone death is a cell autonomous event caused by reduced nutrient uptake, in particular glucose, and showed that cell autonomous activation of the kinase mammalian target of rapamycin complex 1 (mTORC1), by deletion of its negative regulator the tuberous sclerosis complex protein 1 (TSC1), significantly prolongs cone survival. Since our initial findings others have also supported the notion that secondary cone death in retinitis pigmentosa is manly caused by a shortage of glucose in cones. Our cell autonomous activation of mTORC1 in cones promoted cone survival by improving the following 3 glucose related processes: uptake, retention and metabolism. In this grant we want to test to which extent each of these 3 processes contributes to cone survival. We have identified 3 genes, through a rational analysis of our data, each representing one of these 3 processes. Here we propose to test how much each gene contributes to cone survival by rAAV mediated gene transfer to cones. We will test the cone survival effect mediated by each gene individually and in combination of two genes at the same time. To ensure that our approach is mutation independent we will carry out our experiments in two mouse models of retinitis pigmentosa. Accomplishment of the proposed research will lay the foundation for the design of a rational therapeutic approach to extend vision in humans with retinitis pigmentosa.
PI: Claudio Punzo Project Narrative Retinitis pigmentosa is an inherited retinal degenerative disease that is untreatable and leads to blindness. Most disease causing mutations encode for genes that are exclusively expressed in the night active rods. Consequently, night blindness is the first pathological sign of the disease. However, even though the mutation does not affect a gene that is expressed in the day active cones, loss of rods results eventually in tunnel vision and then complete blindness. We have recently shown that during cone death cones are nutritionally deprived due to a lack of glucose, and that activation of cell metabolism in cones promotes cone survival. Here we propose to directly test a gene therapy approach with 3 metabolic genes in order to assess the potential of these 3 genes as a therapeutic strategy to prolong vision in retinitis pigmentosa.
