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Elisabeth Obert, Gautam Ghatnekar, Baerbel Rohrer; Effects of the Act-1 Peptide on Retinal Pigment Epithelial Cell Integrity in Two Mouse Models of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2341. doi: https://doi.org/.
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Age-related macular degeneration (AMD) is a multifactorial disease and is regarded as the predominant cause of central vision loss in industrialized countries. The main target tissue is the retinal pigment epithelium (RPE), which together with the Bruch’s membrane forms the blood-retina barrier. Zonula Occludens-1 (ZO-1) interacts with various cell junction proteins, contributing to RPE cell junction function. RPE-barrier dysfunction and blood vessel leakage associated with AMD might result from altered ZO-1 function. Designed to regulate ZO-1’s interactions with its respective binding partners, a synthetic peptide Act-1 (Alpha connexin carboxy terminus) was developed that competes for the binding of ZO-1. We examined the effects of Act-1 in two murine in vivo AMD models.
Choroidal neovascularization (CNV) was induced using laser-photocoagulation; RPE-cell barrier loss was triggered by bright light exposure (3000 lux for 3 hours). Both models lead to VEGF-dependent loss of cell junctions. The Act-1 peptide was delivered via daily eyedrops (10 mL, 5 mM). CNV lesion sizes were determined using optical coherence tomography (OCT). RPE flatmounts were stained for cell-junction proteins ZO-1, Occludin and ZONAB (ZO-1-associated nucleic acid binding protein). Cell profiler software was used to examine the RPE tiling pattern.
OCT analysis demonstrated that treatment with Act-1 reduced CNV development (Act-1: 3845 ± 337, PBS: 5519 ± 312; p<0.5). CNV size was correlated with RPE cell integrity. In PBS-treated animals, ZO-1, occludin and ZONAB-staining revealed a large halo of unhealthy RPE cells surrounding the CNV lesion, the diameter of which was significantly reduced by ~ 30% by ACT-1 (P<0.01). 24 hours after light-damage, RPE cell morphology was significantly disrupted in PBS treated animals (loss of cell junction markers, larger and irregular shapes), while RPE cells from Act-1 treated mice maintained a healthy morphology.
Taken together, Act-1 peptide was effective in ameliorating RPE dysfunction in both models. Future research will include investigating the peptide’s mechanism of action.
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