September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Targeting the tight junction protein, zonula occludens-1, with the connexin 43 mimetic peptide, αCT1, reduces VEGF-dependent RPE pathophysiology
Author Affiliations & Notes
  • Elisabeth Obert
    Medical University of South Carolina, Charlestobn, South Carolina, United States
  • Robert Gourdie
    Virginia Tech Carilion Research Institute, Roanoke, Virginia, United States
  • Gautam Ghatnekar
    First String Therapeutics, Mount Pleasant, South Carolina, United States
  • Baerbel Rohrer
    Medical University of South Carolina, Charlestobn, South Carolina, United States
    Ralph H. Johnson VA Medical Center, Charleston, South Carolina, United States
  • Footnotes
    Commercial Relationships   Elisabeth Obert, First String Therapeutics (R); Robert Gourdie, First String Therapeutics (P); Gautam Ghatnekar, First String Therapeutics (E), First String Therapeutics (P); Baerbel Rohrer, First String Therapeutics (P)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4993. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Elisabeth Obert, Robert Gourdie, Gautam Ghatnekar, Baerbel Rohrer; Targeting the tight junction protein, zonula occludens-1, with the connexin 43 mimetic peptide, αCT1, reduces VEGF-dependent RPE pathophysiology. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4993.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : A critical target tissue in age-related macular degeneration (AMD) is the retinal pigment epithelium (RPE), which together with Bruch’s membrane forms the outer blood-retina barrier (BRB). RPE-barrier dysfunction in AMD might result from attenuation and disruption of intercellular tight junctions. Zonula occludens-1 (ZO-1) is a major structural protein of intercellular junctions. A connexin-based peptide mimetic, αCT1 (Alpha Connexin carboxy-Terminal 1), was developed which competitively inhibits ZO-1 interaction with its binding partners. We hypothesized that targeting ZO-1 signaling using αCT1 would maintain BRB integrity and reduce RPE pathophysiology by stabilizing gap- and/or tight-junctions.

Methods : Choroidal neovascularization (CNV) was induced using laser-photocoagulation; RPE-cell barrier loss was triggered by bright light exposure. Both models lead to VEGF-dependent cell damage. αCT1 was delivered via eyedrops. CNV size and fluid leakage were determined using optical coherence tomography. RPE flatmounts were stained for ZO-1 and occludin, and tiling patterns analyzed (CellProfiler). ARPE-19 monolayers were used to evaluate αCT1’s mechanism of action in response to VEGF exposure.

Results : αCT1 treatment reduced CNV development and fluid leakage, and damage was correlated with disruption in cellular integrity of the surrounding RPE cells. Light-damage significantly disrupted RPE cell morphology, which was prevented by αCT1 pre-treatment. In vitro experiments using ARPE-19 cell monolayers suggest that αCT1 stabilizes intercellular tight junctions.

Conclusions : Taken together, stabilization of cellular junctions with αCT1 was effective in ameliorating RPE dysfunction in AMD models of photo-coagulation-induced CNV and bright-light exposure RPE-cell barrier loss. Future research will include additional investigation into the peptide’s mechanism of action.

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.

×