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Rania Sulaiman Sulaiman, Bit Lee, Wei Sun, Khoa Trinh, Seung-Yong Seo, Timothy William Corson; A novel inhibitor of soluble epoxide hydrolase synergizes with anti-VEGF therapy in suppressing choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1108.
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© 2017 Association for Research in Vision and Ophthalmology.
Choroidal neovascularization is the vision-threatening characteristic of wet age-related macular degeneration (AMD), a major cause of blindness. Current treatments target vascular endothelial growth factor (VEGF) signaling. However, the development of small molecule treatments targeting different angiogenic pathways is crucial to complement the existing biologic therapies. We previously developed the anti-angiogenic compound SH-11037 with potency and selectivity in vitro on human retinal endothelial cells (HRECs). Moreover, intravitreally injected SH-11037 suppressed angiogenesis in the laser-induced choroidal neovascularization (L-CNV) model without ocular toxicity. Here, we characterized a molecular target of SH-11037 and tested the therapeutic potential of SH-11037/anti-VEGF combinations in vitro and in vivo.
Photoaffinity pulldown was used to elucidate SH-11037’s target, with subsequent enzyme activity assay. Combinations of SH-11037 and aflibercept were evaluated in vitro on HREC proliferation using alamarBlue fluorescence. Eight week old mice received laser burns and intravitreal injections of vehicle, SH-11037, anti-VEGF164 or SH-11037/anti-VEGF combinations. After 14 days, eyes were enucleated and choroids were stained with agglutinin and CNV lesion volumes were calculated from Z-stack confocal images.
Photoaffinity pulldown revealed soluble epoxide hydrolase (sEH) as a protein target of SH-11037. This was confirmed by immunoblot and inhibition of sEH enzymatic activity. Identification of sEH as SH-11037’s target suggests a VEGF-independent mechanism of action; therefore, we tested SH-11037/anti-VEGF combinations. An SH-11037/aflibercept combination inhibited HREC proliferation more than each treatment alone. Moreover, combining two individually inactive doses of SH-11037 and anti-VEGF164 in vivo significantly suppressed L-CNV lesions. SH-11037/anti-VEGF combinations tested in vitro and in vivo appeared synergistic according to excess over highest single agent and Bliss additivity analyses.
These data demonstrate that SH-11037 is VEGF independent and synergistic with anti-VEGF. SH-11037 interacts with and inhibits the enzymatic activity of sEH, a known inflammatory and angiogenic mediator. As a novel inhibitor of sEH, SH-11037 could be used in combination with the standard anti-VEGF for the treatment of wet AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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