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Songhua Li, Marijana Samardzija, Zhihui Yang, Christian Grimm, Minghao Jin; Sodium 4-Phenylbutyrate Improves Cone Survival and Function in a Mouse Model for Leber Congenital Amaurosis. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3623.
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© ARVO (1962-2015); The Authors (2016-present)
Similar to patients with RPE65 mutations, the R91W knock-in mouse model of LCA exhibits severe cone degeneration and vision impairment. We have shown that the R91W RPE65 undergoes rapid proteasomal degradation due to misfolding. In this study, we tested whether Sodium 4-Phenylbutyrate (PBA), a chemical chaperone, can ameliorate cone survival and function in the mutant mouse.
Ocular retinoids in wild-type and R91W mice treated systemically with sodium 4-phenylbutyrate (PBA) or saline were analyzed by high-performance liquid chromatography. Expression levels of RPE65, cone arrestin (CAR), and cone opsins were determined by quantitative immunoblot analysis. S-opsin mislocalization and numbers of surviving cones in R91W mice were determined by retinal immunohistochemistry using antibodies against S-opsin, CAR or M-opsin. Cone visual function was evaluated by photopic ERG responses evoked by white and UV light flashes.
Retinyl esters were dramatically accumulated in the eyes of R91W mice, compared to wild-type mice. Treatment of R91W mice with PBA reduced the accumulation as compared to saline-treated R91W mice. In contrast, 11-cis-retinal and 9-cis-retinal, a functional iso-chromophore of the visual pigments, were increased in R91W mice treated with PBA. PBA-treatment also significantly reduced S-opsin mislocalization in R91W retina. Protein levels of S-opsin, CAR and M-opsin were significantly increased in PBA-treated versus saline-treated R91W mice. Consistent with this result, the numbers of CAR-positive cones and M-cones in the inferior retina of R91W mice treated with PBA were significantly greater than those in saline-treated R91W mice. Importantly, PBA-treatment also improved cone-mediated vision in R91W mice.
PBA, a FDA-approved oral medication, is a non-invasive therapeutic candidate that not only can be used alone but also can supplement RPE65 gene therapy to delay cone vision loss in patients with RPE65 mutations.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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