Restoration of Cone Photoreceptor Function in Retinitis Pigmentosa

The major cause of hereditary blindness in North America is retinitis pigmentosa (RP), which is a group of inherited diseases of the retina characterized by the onset of night blindness, the early loss of the peripheral visual field, and the late loss of central vision. In the late stage of the disease when retinal degeneration approaches the macula and cone degeneration ensues, most patients find themselves with a profoundly incapacitating visual handicap because of the loss of central vision which precedes this stage of the disease, is also debilitating (e.g., for driving motor vehicles and reading). If therapy can prevent or reverse the onset of cone degeneration within the macula most patients would be immeasurably helped and able to live a normal life despite the loss of peripheral vision and decreased dark adaptation. Over 67 mutant genes (www.sph.uth.tmc.edu/Re tNet/home.htm) have been identified in monogenic forms of RP, all leading to generally similar photoreceptor pathology. Some of these mutations arise in genes, such as RHO that play a direct role in rod visual transduction, and ROM1 that contribute to visual pigment-rich outer segment (OS) structure. But, other mutations arise in seemingly unrelated pathways including metabolism and RNA processing. And, even rod-autonomous mutations in retinal pigment epithelial (RPE)-specific genes can give rise to RP. How these disparate target genes expressed in both rods and RPE are linked into a seemingly common RP-sensitive pathway remains a crucial unanswered question including the loss of a highresolution central cone vision in end-stage RP. It is still unclear why cones lose function as rods began to die during RP progression. Mutant RHO becomes trapped in the endoplasmic reticulum (ER) and the rods undergo apoptosis. With rod degeneration, cone photoreceptors begin to lose function. Diminished cone function is highlighted by loss of functional structures, including visual pigment-rich OS and mitochondrial–rich inner segments (IS). Importantly, in contrast to rod cell bodies that die during rod photoreceptor degeneration there is long-term persistence of cone cell bodies after cone photoreceptor degeneration with little more than residual cone nuclei in RP patients, referred to as cone dormancy (Fig. 1). Photoreceptors are among the most metabolically active cells, and like other neurons, depend on glucose, which is thought to be critical not only for energy production but for OS synthesis. The importance of glycolysis in both rod and cone photoreceptors can be illustrated by inhibition of the essential glycolytic pathway enzyme glyceraldehyde 3-phosphate dehydrogenase with iodoacetic acid and enhancing photoreceptor glycolysis by mutation of Sirt6 or overexpression of rod-derived cone viability factor (RdCVF), which promotes glucose uptake into cones to enhance glycolysis. Following a glycolytic block, both rods and cones rapidly lost OS. As the glycolytic block diminished, dormant cones resumed OS synthesis and function, but rods failed to do so and died. By contrast,