Cone Rescue in Retinitis Pigmentosa

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Project Summary/Abstract A major cause of blindness in North America is hereditary retinal degeneration and Retinitis Pigmentosa (RP) is the leading cause. RP is a group of inherited diseases characterized by the onset of night blindness, the early loss of the peripheral visual field, and ultimately the loss of central vision. The most common form of autosomal dominant form of RP is caused by a Pro23His mutation in rhodopsin that results in retinal degeneration – i.e. P23H retinopathy. We have created and characterized a miniature pig model of P23H retinopathy to investigate therapeutic options to prevent or delay the onset of visual loss. Multiple therapeutic approaches have been or are being considered to prevent/delay the progression of RP, including cell-based, gene and drug therapies. Gene transfer in Leber's Congenital Amaurosis (LCA), a small subset of RP patients, shows very strong therapeutic promise. That said, gene therapy for other forms of RP faces several challenges including the wide variety of mutations associated with the disease. Cell–based transplantation of rod photoreceptors derived from a number of sources seeks to reverse the progression of RP. Although the early stage of RP is marked by the onset of rod degeneration in mid- peripheral retina, only in the late stages of the disease when retinal degeneration approaches the macula and cone degeneration ensues do most patients find themselves with a severe visual handicap. It also is well established that in RP, cone survival depends on normal rods. We have preliminarily observed that transplanted rod photoreceptors derived from pig induced Pluripotent Stem Cells (iPSCs) injected beneath the retina in our pig model of P23H retinopathy will rescue cones morphologically and functionally in the area centralis (analogous to the macula in man). We will confirm this observation, explore the synergistic effect of neuroprotection with rod derived cone viability factor (RdCVF) and further investigate the mechanism of cone loss in our model. Our studies have the potential to prevent the onset of functional blindness in the majority of patients with RP, not only those with the P23H mutation.