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Jerome Cole II, Sufiya Khanam, Koushik Mondal, Sandip K Basu, Kaining Zhi, Harry Kochat, Kennard Brown, Nawajes A Mandal; Sphingolipid Modulators as Retinitis Pigmentosa Therapeutics. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4284.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis Pigmentosa (RP) is an incurable and untreatable group of heterogeneous retinal neurodegenerative diseases that cause progressive dysfunction and death of retinal photoreceptor cells. Currently, there are no therapeutics that substantially slows the progression of this disease or can restore vision in RP patients. Our previous research identified a common mediator, that is involved in the process of photoreceptor cell death, which could be targeted to prevent, or delay, RP progression. We identified retinal ceramides (Cer), the signaling sphingolipid, a potent mediator of cell death, increases in the retina and facilitates the retinal cell death process. We hypothesized, regardless of the causal factor/gene mutation, ceramide could be targeted to prevent and/or delay photoreceptor cell death. The purpose of this study was to determine the preventive effect of Cer biosynthetic inhibitor, FTY720, in mouse model of RP. We utilized RD10 mouse model that carries a mutation in the Pde6b gene that leads to photoreceptor dysfunction and eventual loss of photoreceptor cells by apoptosis.
RD10 mice were administered 2.5 mg/kg of FTY720 systemically twice/week beginning at P10 and ending at P60. Littermates were administered 12.5% DMSO as a Control. The visual and retinal functions were monitored by Optokinetic Tracking (OKT) and Electroretinography (ERG) respectively at P30, P45 and P60. Eyes were enucleated for histology at same intervals and retinal integrity were determined by histology.
In RD10 mouse model the rapid retinal degeneration is associated with an increase of Cer in retinal tissues by P15 through P30. We observed a reduction in Cer levels in the retina of FTY720 treated animals. Significant preservation of visual acuity was observed at P45 and P60 in treated animals compared to controls. Retinal ERG -A and B wave amplitudes were significantly preserved in treated mice at P30 and P45. Histological analysis revealed preservation of higher number of photoreceptor nuclei at P30 of the treated animals.
Our study clearly demonstrates that FTY720 could lead to preservation of vision in animal model of retinal degeneration. It further established that a reduction in Cer level in the retina could prevent photoreceptor apoptosis and functional vision loss.
This is a 2020 ARVO Annual Meeting abstract.
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