Delaying Cone Death in Retinitis Pigmentosa

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DESCRIPTION (provided by applicant): 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 cone death always follows rod death, and 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 and showed that the insulin/AKT/mTOR pathway plays a crucial role during the periods of cone death. Systemic administration of insulin to retinitis pigmentosa mice prolongs cone survival. Here we propose to study how insulin prolongs cone survival. To that end we have now genetically activated the pathway in cones, by deletion of the phosphatase and tensin homolog (PTEN) and separately, by deletion of the tuberous sclerosis complex protein 1 (TSC1). Loss of PTEN or TSC1 further improves cone survival when compared to insulin administration, suggesting that genes downstream of PTEN and TSC1 have therapeutic potential to prolong vision in retinitis pigmentosa. Since loss of PTEN or TSC1 activates the kinases mechanistic target of rapamycin (mTOR) and AKT, genes that promote cone survival are predicted to be downstream of these two kinases. Because mTOR and AKT have hundreds of targets we will first delineate the contribution of these two kinases to cone survival seen upon loss of PTEN or TSC1. These experiments will be carried out in aims 1 & 2. Subsequently, in aim 3 we will use microarrays to identify target genes of mTOR and/or AKT that promote cone survival. Finally, we will tests the efficacy of such genes in vivo using recombinant Adeno-associated virus mediated gene transfer. Accomplishment of these aims will help design rational therapeutic approaches to extend vision in humans with retinitis pigmentosa.