CYP2C8: a target for treating and preventing vascular diseases of the retina
Inventors: Lois Smith, Zhuo Shao
Invention Types: Therapeutics
Research Areas: Oncology/Hematology, Ophthalmology
Keywords: Drug Discovery, Small Molecule/DrugFor More Information Contact: Yen, Alan
Retinal neovascularization, the abnormal formation of excessive blood vessels within the eye, is a chief cause of various vision-impairing diseases including diabetic retinopathy, age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). These diseases account for a significant proportion of blindness cases around the world.
Previous work in an oxygen-induced retinopathy (OIR) mouse model demonstrated that neovascularization can be suppressed by a diet rich in Omega-3LCPUFAs (Omega-3-long-chain polyunsaturated fatty acids) due to the anti-angiogenic metabolites of cyclooxygenase and lipoxygenase.
Interestingly, Dr. Smith and colleagues found that Cytochrome P450 epoxygenases (CYP2C8) can also metabolize Omega-3LCPUFAs, producing various angiogenic epoxides, which are inactivated and converted to transdihydrodiols by the enzyme, soluble epoxide hydrolase (sEH). In a model of OIR, the researchers observed an upregulation of CYP2C8 and a suppression of sEH, consistent with an increased ratio of retinal epoxide:diol, the byproducts of the reaction pathway. They further explored this association in CYP2C8-overexpressing mice, and in sEH-overexpressing mice subjected to a Omega-3LCPUFA enriched diet. In CYP2C8-overexpressing mice, they found an increase in retinal neovascularization associated with a greater ratio of epoxide:diol and plasma concentration of 19,20-epoxydocosapentaenoic acid. In sEH-overexpressing mice, they observed a decrease in this ratio and concentration. These results strongly suggest that CYP2C8 and sEH are part of a novel lipid metabolic pathway that modulates retinal neovascularization.
• Inhibition of CYP2C8 presents a novel target for retinopathy treatment.
• The present invention is based, in part, on the novel finding that CYP2C8/sEH metabolism of LCPUFAs regulates neovascularization in oxygen-induced retinopathy (OR), corresponding to an increased epoxide:diol ratio.
• Therapeutics targeting CYP2C8 may inhibit the production of angiogenic metabolites from both Omega-3LCPUFA and Omega-6LCPUFA.
• Inhibitors of CYP2C8 may also be used for non-ocular disorders characterized by neovascularization, such as various cancers and inflammatory disorders.
• Therapeutics may be administered in concert with other interventions, such as photodynamic procedures.
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Gong Y, Fu Z, Liegl R, et al. ω-3 and ω-6 long-chain PUFAs and their enzymatic metabolites in neovascular eye diseases. Am J Clin Nutr. 2017 Jul;106(1):16-26.
Gong Y, Fu Z, Edin ML, et al. Cytochrome p450 Oxidase 2C inhibition adds to ω3-long-chain polyunsaturated fatty acids protection against retinal and choroidal neovascularization. Anterioscler Thromb Vasc Biol. 2016 Sep;36(9):1919-27.
Shao Z, Fu Z, Stahl A, et al. Cytochrome P450 2C8 ω3-long-chain polyunsaturated fatty acid metabolites increase mouse retinal pathologic neovascularization – brief report. Anterioscler Thromb Vasc Biol. 2014 Mar;34(3):581-6.
IPStatus: Pat. Pend.