September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
A novel inhibitor of soluble epoxide hydrolase synergizes with anti-VEGF therapy in suppressing choroidal neovascularization
Author Affiliations & Notes
  • Rania Sulaiman Sulaiman
    Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Bit Lee
    Pharmacy, Gachon University, Seoul, Korea (the Republic of)
  • Wei Sun
    Pharmacy, Gachon University, Seoul, Korea (the Republic of)
  • Khoa Trinh
    Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Seung-Yong Seo
    Pharmacy, Gachon University, Seoul, Korea (the Republic of)
  • Timothy William Corson
    Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Footnotes
    Commercial Relationships   Rania Sulaiman, 62/259,281 (P); Bit Lee, 14/888,117 (P); Wei Sun, None; Khoa Trinh, None; Seung-Yong Seo, 14/888,117 (P); Timothy Corson, 14/888,117 (P), 62/259,281 (P)
  • Footnotes
    Support  International Retinal Research Foundation, Research to Prevent Blindness, Inc. NIH NCATS UL1TR001108
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 1108. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      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.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : 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.

Methods : 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.

Results : 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.

Conclusions : 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.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×