Decreased Expression of Soluble Epoxide Hydrolase Suppresses Murine Choroidal Neovascularization

Author:

Park BominaORCID,Sardar Pasha Sheik Pran Babu,Sishtla Kamakshi L.ORCID,Hartman Gabriella D.ORCID,Qi Xiaoping,Boulton Michael E.ORCID,Corson Timothy W.ORCID

Abstract

Neovascular or “wet” age-related macular degeneration (nAMD) is a leading cause of blindness among older adults. Choroidal neovascularization (CNV) is a major pathological feature of nAMD, in which abnormal new blood vessel growth from the choroid leads to irreversible vision loss. There is a critical need to develop novel therapeutic strategies to address limitations of the current anti-vascular endothelial growth factor biologics. Previously, we identified soluble epoxide hydrolase (sEH) as a possible therapeutic target for CNV through a forward chemical genetic approach. The purpose of this study was to validate sEH as a target by examining retinal expression of sEH protein and mRNA by immunohistochemistry and RNAscope in situ hybridization, respectively, and to assess the efficacy of an adeno-associated virus (AAV) vector designed to knock down the sEH gene, Ephx2, in the murine laser-induced (L-) CNV model. nAMD patient postmortem eye tissue and murine L-CNV showed overexpression of sEH in photoreceptors and retinal pigment epithelial cells. Ephx2 knockdown significantly reduced CNV and normalized mRNA expression levels of CNV-related inflammatory markers. Thus, this study further establishes sEH as a promising therapeutic target against CNV associated with nAMD.

Funder

Retina Research Foundation

NIH/NEI

Carl Marshall Reeves & Mildred Almen Reeves Foundation

Indiana Center for Biomedical Innovation

Research to Prevent Blindness

Eli Lilly-Stark Neurosciences Predoctoral Research Fellowship in Neurodegeneration

PhRMA Foundation Predoctoral Fellowship in Pharmacology/Toxicology

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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