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 (ARMD) 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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Key Publications: Shao Z, Fu Z, Stahl A, Joyal J-S, Hatton C, Juan A, Hurst C, Evans L, Cui Z, Pei D, Gong Y, Xu D, Tian K, Bogardus H, Edin ML, Lih F, Sapieha P, Chen J, Panigrahy D, Hellstrom A, Zeldin DC, Smith LEH, 2014. Cytochrome P450 2C8 ω3-Long-Chain Polyunsaturated Fatty Acid Metabolites Increase Mouse Retinal Pathologic Neovascularization – Brief Report (published online before print Jan. 23, 2014). Arteriosclerosis, Thrombosis, and Vascular Biology 34: 581-586.
IPStatus: Pat. Pend.