June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Secretogranin III as a novel disease-associated target for anti-angiogenic therapy of diabetic retinopathy
Author Affiliations & Notes
  • Wei Li
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
    Everglades Biopharma, Miami, Florida, United States
  • Michelle LeBlanc
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
    Everglades Biopharma, Miami, Florida, United States
  • Weiwen Wang
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Xiuping Chen
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
    Ophthalmology, Zhongshan Hospital, Shanghai, Shanghai, China
  • Nora Blanca Caberoy
    School of Life Sciences, University of Nevada Las Vegas, Las Vegas, Nevada, United States
  • Chen Shen
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Yanli Ji
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Hong Tian
    Everglades Biopharma, Miami, Florida, United States
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Hui Wang
    Baylor College of Medicine, Houston, Texas, United States
  • Rui Chen
    Baylor College of Medicine, Houston, Texas, United States
  • Footnotes
    Commercial Relationships   Wei Li, Founder - Everglades Biopharma (S), Inventor - University of Miami (P), Spouse - Everglades Biopharma (S); Michelle LeBlanc, Cofounder - Everglades Biopharma (S), Inventor - University of Miami (P); Weiwen Wang, Inventor - University of Miami (P); Xiuping Chen, None; Nora Caberoy, None; Chen Shen, None; Yanli Ji, None; Hong Tian, Co-founder - Everglades Biopharma (S), Spouse - Everglades Biopharma (S); Hui Wang, None; Rui Chen, None
  • Footnotes
    Support  NIH R01GM094449; R21EY027065; AHA 16PRE27250308
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4028. doi:
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      Wei Li, Michelle LeBlanc, Weiwen Wang, Xiuping Chen, Nora Blanca Caberoy, Chen Shen, Yanli Ji, Hong Tian, Hui Wang, Rui Chen; Secretogranin III as a novel disease-associated target for anti-angiogenic therapy of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4028.

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

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Abstract

Purpose : Vascular endothelial growth factor (VEGF) inhibitors have been approved for diabetic macular edema (DME) therapy but with limited efficacy. The purpose of this study is to identify unknown vascular permeability factors (VPFs) and develop novel therapies for diabetic retinopathy (DR).

Methods : We applied a new technology of ligandomics to diabetic or control mice for global identification of cell-wide retinal endothelial ligands. Quantitative comparison of the entire ligand profiles for diabetic vs. control retina systematically identified ligands with increased or decreased binding to diabetic endothelia. Identified ligands were independently verified as VPFs by in vitro endothelial permeability assay. Disease-associated angiogenic activity was verified by corneal pocket assay in diabetic or control mice. Monoclonal antibodies (mAb) were generated. Therapeutic agents were intravitreally injected to evaluate their ability to inhibit retinal vascular leakage using Evans blue assay.

Results : Comparative ligandomics systematically identified 353 ligands with increased binding (DR-high) to diabetic retinal endothelia and 105 ligands with decreased binding (DR-low). Secretogranin III (Scg3) was identified as a DR-high ligand with the highest binding activity ratio for diabetic vs. control retina (1,731:0, p<0.0001, c2 test). Scg3 was upregulated in the vitreous fluid of diabetic mice only by 1.38-fold (p<0.05). We independently verified Scg3 as a novel VPF. Scg3 was corroborated as a DR-high ligand that selectively stimulated corneal angiogenesis in diabetic but not control mice. In contrast, VEGF induced angiogenesis in both diabetic and control mice. Scg3 induced angiogenesis through a VEGF-independent receptor pathway. Intravitreal injection of Scg3-neutralizing mAb significantly alleviated retinal vascular leakage in two independent mouse models of DR with high efficacy (p<0.01).

Conclusions : Scg3 was previously reported as a protein to regulate secretory granule biogenesis and has not hitherto been described as a cellular ligand. This study discovers Scg3 as a novel and highly disease-associated VPF and angiogenic factor. Scg3-neutralizing mAb ameliorates DR leakage with high efficacy, implicating its potential for DME therapy. These results also demonstrate the validity and utility of the comparative ligandomics for systematic mapping of therapeutic ligands.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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