Indiana University-Purdue University Indianapolis (IUPUI) / Choroidal neovascularization (CNV) is the vision-threatening characteristic of wet
age-related macular degeneration (AMD), a major cause of blindness affecting
almost 2 million elderly Americans. The current approved treatments target the
dominant angiogenic mediator, vascular endothelial growth factor (VEGF).
However, repeated injections of anti-VEGF drugs can cause ocular and systemic
side effects, and about 30% of wet AMD patients are non-responsive. There is
thus an unmet need to develop VEGF-independent antiangiogenic molecules to
complement or combine with existing medications.
I studied SH-11037, a novel homoisoflavonoid with potent and selective
antiangiogenic activity against human retinal endothelial cells. Intravitreal SH-
11037 dose-dependently suppressed angiogenesis in the laser-induced CNV (LCNV)
mouse model. These effects were prominent as early as 7 days post-laser
treatment as measured by a novel ellipsoid quantification method of optical
coherence tomography images in vivo. A supratherapeutic dose of 100 μM SH-
11037 was not associated with signs of murine ocular toxicity, and did not
interfere with pre-existing retinal vasculature or retinal function. SH-11037
synergized with anti-VEGF therapy in vitro and in vivo, suggesting a VEGFindependent
mechanism. By photoaffinity pulldown, I identified soluble epoxide hydrolase (sEH) as an SH-11037-binding target. sEH is a key enzyme in ω-3 and
ω-6 fatty acid metabolism. sEH levels were dramatically upregulated in retinal
sections from L-CNV mice and a specific sEH inhibitor, t-AUCB, significantly
suppressed L-CNV lesion volume. Additionally, SH-11037 inhibited sEH
enzymatic activity in vitro and in vivo in L-CNV mice. Given the role of sEH in the
metabolism of docosahexaenoic acids (DHA), inhibition of sEH using small
molecules like SH-11037 would enhance ocular DHA levels, with beneficial
antiangiogenic and anti-inflammatory effects. SH-11037 is thus a novel sEH
inhibitor, which could make it an alternative or additive therapy to existing anti-
VEGF drugs for treatment of neovascular diseases in the eye and other tissues.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/10604 |
| Date | 24 May 2016 |
| Creators | Sulaiman, Rania S. |
| Contributors | Corson, Timothy W., Cummins, Theodore R., Jerde, Travis J., Lu, Tao, Boulton, Michael E. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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