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Timothy Corson, PhD
BASIC RESEARCH PROJECT
Dr. Corson’s Research Project
“Role of epoxy lipid metabolism in choroidal neovascularization”
Current Research Interests
Existing antiangiogenic drugs for diseases like wet AMD all target the same pathophysiological mechanism: vascular endothelial growth factor (VEGF) signaling. Although these biologics are effective therapies in many cases, incomplete response and significant ocular and non-ocular side effects complicate their use. There is thus a critical need for novel antiangiogenic targets that might allow development of new agents that complement and combine with existing approaches. The overall goal of this project is to develop novel therapeutic approaches for ocular neovascularization. An intriguing target for drug discovery is the lipid metabolism enzyme sEH, which, with prior RRF, funding, Dr. Corson identified as a target of his novel antiangiogenic compound SH-11037 and which is overexpressed in choroidal neovascularization (CNV). The overall objective of this project is to evaluate how sEH inhibition blocks CNV.
Progress in 2016
“Soluble epoxide hydrolase: a therapeutic target in choroidal neovascularization?”
Homoisoflavonoids are a small class of natural products that Dr. Corson has pursued as antiangiogenic leads. In particular, he focused on a target of SH-11037 that he identified, soluble epoxide hydrolase (sEH), hypothesizing that sEH is required for choroidal neovascularization. He has completed the Aim 1 of assessing sEH expression in murine and human choroidal neovascularization, and most of Aim 2, inhibiting sEH in the context of choroidal neovascularization. It will be important to determine what aspects of sEH function are important for blood vessel growth, and how this enzyme is linked to signaling in the cell. Dr. Corson proposes to do these experiments during the 2017 grant period. This work will lay the groundwork for future efforts to target sEH for the treatment of wet AMD and related retinal diseases of abnormal blood vessel growth.
Plans for 2017
Dr. Corson plans to focus in 2017 on deciphering how the SH=11037 target sEH regulates CNV. He will assess the therapeutic and biological effects of introducing the sEH substrate and product into the eye in the context of L-CNV, and determine the downstream signaling modulated by sEH inhibition. The proposed work will continue to move this project in a translational direction by delineating how sEH is important for neovascularization, with the aim of finding further points in this mechanism for therapeutic intervention. Specific Aim) Assess the effects of an sEH substrate and product on CNV and angiogenic signaling. He will treat eyes undergoing L-CNV with 19,20-EDP and 19,20-DHDP, with or without t-AUCB or SH-11037 treatment, and compare the neovascular responses.
Progress in 2015
“Synergistic effects of a novel antiangiogenic molecule”
Dr. Corson’s laboratory has tested their most potent synthetic homoisoflavanone, SH-11037, in combination with anti-VEGF therapy. It showed efficacy comparable to the standard anti-VEGF treatment in the laser-induced choroidal neovascularization (L-CNV) mouse model, which models some of the features of wet AMD. SH-11037 could synergize with anti-VEGF, reducing the amount of each drug needed for an effect. Importantly, they saw no short-or long-term toxicity in the eyes of adult mice with SH-11037 injected into their eyes. They have begun to tease apart how SH-11037 works to block blood vessel growth, and have identified an enzyme called soluble epoxide hydrolase (sEH) as a target of SH-11037. It will be important to assess if sEH is found at high levels in CNV, and if blocking its function can decrease L-CNV. Dr. Corson proposes to do these experiments during the 2016 grant period.
Progress in 2014
“Testing a novel Antiangiogenic molecule in a mouse model of retinopathy of prematurity”
Previously with RRF funding, Dr. Corson investigated a class of natural products, homoisoflavonoids, as antiangiogenic molecules. He synthesized a naturally occurring, antiangiogenic homoisoflavanone called Cremastranone derived from a medicinal orchid species and a novel isomer, both of which showed antiangiogenic activity in vitro. He has tested a novel, more potent derivative of Cremastranone called SH-11037 in the oxygen-induced retinopathy (OIR) model of ROP. It showed efficacy comparable to the standard anti-VEGF treatment. Importantly, he saw no short- or long-term toxicity in the eyes of adult mice intravitreally injected with SH-11037, and the compound was also effective in the laser-induced choroidal neovascularization (L-CNV) mouse model. Dr. Corson has begun to tease apart how SH-11037 works to block blood vessel growth.
Progress in 2013“Cellular target of a candidate AMD therapy”
Previously with RRF funding, Dr. Corson investigated a class of natural products, homoisoflavonoids, as antiangiogenic molecules. He synthesized a novel isomer (SH-11052) of a naturally occurring, antiangiogenic homoisoflavanone derived from a medicinal orchid species and showed Antiangiogenic activity of SH-11052 in vitro. In the course of these studies, Dr. Corson’s laboratory developed a compound SH-11037, a novel therapeutic lead based on the natural product, but with improved efficacy and specificity. SH-11037 potently and specifically blocks human retinal microvascular endothelial cell (HRMVEC) proliferation, migration, and tube formation in vitro by a molecular mechanism distinct from other homoisoflavonoids, but has little cytotoxic effect on other ocular cell lines and does not promote apoptosis. In a small pilot experiment, SH-11037 showed Antiangiogenic activity in the oxygen-induced retinopathy (OIR) model of ROP.