Secretogranin III as a novel target for the therapy of choroidal neovascularization

Exp Eye Res. 2019 Apr;181:120-126. doi: 10.1016/j.exer.2019.01.009. Epub 2019 Jan 8.

Abstract

Wet age-related macular degeneration (AMD) with choroidal neovascularization (CNV) is a leading cause of vision loss in the elderly. The advent of anti-vascular endothelial growth factor (VEGF) drugs represents a major breakthrough in wet AMD therapy but with limited efficacy to improve visual acuity. Secretogranin III (Scg3, SgIII) was recently discovered as a novel angiogenic factor with VEGF-independent mechanisms. Scg3-neutralizing monoclonal antibody (mAb) was reported to alleviate pathological retinal neovascularization in oxygen-induced retinopathy mice and retinal vascular leakage in diabetic mice with high efficacy and disease selectivity. Herein we investigated whether Scg3 is a novel angiogenic target for CNV therapy in mouse models. We found that anti-Scg3 ML49.3 mAb inhibited Scg3-induced proliferation and Src phosphorylation in human retinal microvascular endothelial cells. Intravitreal injection of Scg3-neutralizing polyclonal antibodies (pAb) or mAb significantly attenuated laser-induced CNV leakage, CNV 3D volume, lesion area and vessel density. Furthermore, subcutaneous administration of Scg3-neutralizing pAb or mAb significantly prevented Matrigel-induced CNV. The efficacy of anti-Scg3 pAb or mAb was comparable to VEGF inhibitor aflibercept. These findings suggest that Scg3 plays an important role in CNV pathogenesis and that anti-Scg3 mAb efficiently ameliorates laser- or Matrigel-induced CNV.

Keywords: AMD; Angiogenic factor; Anti-angiogenic therapy; CNV; Choroidal neovascularization; Scg3; Secretogranin III.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antibodies, Neutralizing / pharmacology*
  • Cell Proliferation / drug effects
  • Choroidal Neovascularization / drug therapy*
  • Chromogranins / pharmacology*
  • Disease Models, Animal
  • Endothelial Cells / drug effects*
  • Female
  • Intravitreal Injections
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy / methods*
  • Retina / cytology

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Neutralizing
  • Chromogranins
  • secretogranin III