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Ighovie Felix Onojafe, Haohua Qian, Kiyoharu Miyagishima, Congxiao Zhang, Sheldon S Miller, Brian Patrick Brooks, NEI; Visual function and Nitisinone treatment in a mouse model of OCA1b (Tyr-c-h/c-h). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1487.
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Oculocutaneous albinism (OCA) is an autosomal recessive condition characterized by reduced melanin pigment in the hair, skin, and eyes; decreased best-corrected visual acuity due likely to foveal hypoplasia; abnormal decussation of the optic pathways; and nystagmus. It is unknown why mutations in melanin synthesis genes in the retinal pigment epithelium (RPE) lead to changes in the development of the neural retina (e.g., foveal maturation). We have shown that an FDA-approved drug, nitisinone, can improve the fur and ocular pigmentation in a mouse model of one form of OCA, namely OCA-1B (Onojafe et al, 2011). The purpose of this study is to determine the effect of nitisinone treatment on retinal/RPE function using standard and direct current (DC)-ERGs.
Pregnant female Himalayan mice (C57BL6-Tyrc-h/c-h)—a model of OCA-1B—were treated daily with 4-8mg/kg oral nitisinone (n=7) or vehicle (n=7) beginning at day 10 of pregnancy. After delivery of pups, the nursing mother was treated orally with the same dose every-other-day until weaning (21 days). The pups were then either continued on the same dose of oral nitisinone or vehicle (qod) for an additional month. Standard and DC-ERGs were performed with Espion E2 and Espion E3 respectively, on mice anesthetized with IP injection of ketamine/xylazine and compared to wild-type (WT, C57BL6) controls (n=7).
Treated Himalayan mice exhibited the expected increase in eye and fur melanin pigment. As previously reported, untreated albino mice had slightly larger a- and b- waves compared to WT mice. This small difference was potentially reversed with nitisinone treatment. On DC-ERG testing, WT mice demonstrated a larger c-wave and larger fast osillations compared to untreated Himalayan mice. Intriguingly, these differences could be reversed with nitisinone treatment.
Treatment of Himalayan mice with nitisinone results in measureable changes in the ERG responses of mice. The greatest effect appears to be on the slower c-wave and fast-oscillation responses. These data are consistent with a physiologic change in the RPE as a result of increased melanization and give us a tool to better understand the mechanisms of RPE-mediated retinal development.
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