Photoreceptor death in RP. Upper, simplified time course of rod and cone death kinetics. Time points for possible therapeutic interventions are indicated. Rods can be targeted using an approach specific to a particular disease gene, e.g. by AAV-mediated gene therapy replacing a recessive gene (80, 81, 83) or via knockdown of a dominant gene (13). Alternatively, rod survival can be prolonged by nonspecific therapies, e.g. delivery of growth factors (85, 86) or HDAC4 (14), aimed at a wider group of RP diseases. Cones can be targeted using antioxidant therapy (20, 21) or gene manipulations that might alter metabolism. Once cones have become unable to carry out normal phototransduction, they can be transduced with halorhodopsin, a light-activated chloride pump (64). After the loss of cones, non-photoreceptor cells, such as bipolar cells and retinal ganglion cells, can be made to respond to light following delivery of channel rhodopsin 2 or melanopsin (87, 88). Lower, retinal cross-sections of a mouse model for RP (99) at 8 weeks (wk) and 17 weeks of age. The photoreceptors are located in the outer nuclear layer (ONL), which can be seen to degenerate to one or two rows of cells, primarily cones, by 17 weeks. Note the collapse of the cone OS during this time, revealed by the binding of the lectin peanut agglutinin (PNA; red). Accompanying degeneration is the up-regulation of the glial fibrillary acidic protein (GFAP; rhodopsin; green). INL, inner nuclear layer; GCL, ganglion cell layer.

Metabolism in cones. Photoreceptors are highly active metabolically and require substantial glucose and oxygen, which are supplied by the choroidal vessels via the RPE cells. Lactate may also be released by retinal Müller glia and taken up by photoreceptor cells. Mitochondrial oxidative phosphorylation provides cells with large amounts of ATP for neuronal functions but can also cause an excess of ROS. Removal of ROS requires the actions of the endogenous antioxidative enzymes (superoxide dismutase (SOD), glutathione peroxidase, and catalase) and the natural antioxidant glutathione. The pentose phosphate pathway generates NADPH, which is important for glutathione recycling and lipid synthesis. Sufficient supplies of NADPH, ATP, and the metabolic intermediates ensure rapid macromolecular synthesis, underlying the continuous self-renewal of cone OS. Growth factor signaling, including activation of the insulin receptor, which stimulates mTOR phosphorylation, can positively regulate the key steps of glycolysis. Cones also need NADPH for an early step of the visual cycle, reduction of 11-trans-retinal, which ultimately results in regeneration of 11-cis-retinal. The RPE participates in this cycle, with intermediates cycling between cone OS and the RPE. The major metabolic pathways are highlighted in blue, with the key proteins and molecules of therapeutic interest shown in red.

Schematic representation of rod photoreceptor loss leading to changes in retinal architecture. Before the onset of rod photoreceptor death (A), the interactions between photoreceptor OS and RPE cells are important for photoreceptor nutrient uptake, the visual cycle, and maintenance of photoreceptor structure. When rods first start to die (B), the RPE-OS interactions are not greatly perturbed. However, as the disease progresses (C), the loss of rods becomes very extensive, and the collapse of the remaining cone photoreceptor OS becomes evident. Loss of rods also leads to an elevated oxygen level per cone. D, eventually, the RPE-OS interactions become completely disrupted, which may cause a reduction in nutrient flow, particularly glucose, into the remaining photoreceptors. Cones are shown in blue or red/green, rods in light purple, RPE in pink, and choroid in red.