June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Secretogranin III as a novel angiogenic target for retinopathy of prematurity
Author Affiliations & Notes
  • Michelle LeBlanc
    Bascom Palmer Eye Institute, Miami, Florida, United States
    Everglades Biopharma, Miami, Florida, United States
  • Weiwen Wang
    Bascom Palmer Eye Institute, Miami, Florida, United States
  • Xiuping Chen
    Bascom Palmer Eye Institute, Miami, Florida, United States
  • Nora Blanca Caberoy
    University of Nevada Las Vegas, Las Vegas, Nevada, United States
  • Yanli Ji
    Bascom Palmer Eye Institute, Miami, Florida, United States
  • Hong Tian
    Everglades Biopharma, Miami, Florida, United States
    Bascom Palmer Eye Institute, Miami, Florida, United States
  • Wei Li
    Bascom Palmer Eye Institute, Miami, Florida, United States
    Everglades Biopharma, Miami, Florida, United States
  • Footnotes
    Commercial Relationships   Michelle LeBlanc, Everglades Biopharma (S), University of Miami (P); Weiwen Wang, University of Miami (P); Xiuping Chen, None; Nora Caberoy, None; Yanli Ji, None; Hong Tian, Everglades Biopharma (S), Spouse -Everglades Biopharma (S), University of Miami (P); Wei Li, Everglades Biopharma (S), Spouse -Everglades Biopharma (S), University of Miami (P)
  • Footnotes
    Support  American Heart Association, AHA Award # 16PRE27250308; NIH R01GM094449; R21EY027065
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3454. doi:
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      Michelle LeBlanc, Weiwen Wang, Xiuping Chen, Nora Blanca Caberoy, Yanli Ji, Hong Tian, Wei Li; Secretogranin III as a novel angiogenic target for retinopathy of prematurity. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3454.

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

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Abstract

Purpose : There is currently no approved drug therapy for retinopathy of prematurity (ROP). To address the unmet clinical need, secretogranin III (Scg3) was recently discovered as a novel angiogenic factor with high disease selectivity. Unlike VEGF, Scg3 selectively binds to and induces angiogenesis of diseased but not healthy vessels. In contrast to VEGF, Scg3-/- mice show no adverse effect on vascular and retinal development. The purpose of this study is to characterize Scg3 as a novel target for anti-angiogenic therapy of oxygen-induced retinopathy (OIR) in mice, a surrogate model of ROP.

Methods : Scg3 expression was detected using immunohistochemistry. Scg3 angiogenic activity was evaluated in human retinal microvascular endothelial cells (ECs) using proliferation, tube formation, migration and spheroid sprouting assays. Interactions between Scg3 and VEGF receptors were detected by ELISA and Western blot. An anti-Scg3 monoclonal antibody (mAb) was generated and characterized for its capacity to neutralize Scg3-induced EC proliferation in vitro. To induce OIR, C57BL/6 mice were exposed to 75% oxygen on neonatal Day 7 (P7). After receiving an intravitreal injection of Scg3 mAb or control (0.36 mg/1 ml/eye) on P12, mice were returned to room air. On P17, retinas were isolated, stained with fluorescence-isolectin B4 and analyzed for retinal neovascularization (NV) by confocal microscopy.

Results : Scg3 was detected in the retinal ganglion cells, inner and outer plexiform layers, photoreceptor inner segments and retinal pigment epithelium. Scg3 stimulated EC proliferation (n=4, p<0.01), tube formation (n=4, p<0.01), migration (n=3, p<0.05) and spheroid sprouting (n=8, p<0.001). Scg3 cannot bind to or activate VEGF receptors. Scg3 mAb inhibited Scg3-induced EC proliferation (n=5, p<0.001) and Src activation (n=4, p<0.05). Intravitreally administered Scg3-neutralizing mAb reduced OIR-induced retinal NV (n=11-18, p<0.001), NV tufts (p<0.001) and branching points (p<0.001).

Conclusions : Our results demonstrate that Scg3 is a novel angiogenic factor and that Scg3-neutralizing mAb prevents OIR-induced pathological NV. Owing to the disease selectivity of Scg3 and the normal phenotype of Scg3 knockouts, we predict that anti-Scg3 mAb has the potential for clinical therapy of ROP with minimal side effects on developing retina.

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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