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Frazer Paul Coutinho, Colin R Green, Monica Acosta, Sarah Bould, David Squirrell, Ilva D Rupenthal; The therapeutic potential of XG19 in a mouse model of choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3466. doi: https://doi.org/.
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Choroidal neovascularisation (CNV) is the hallmark of neovascular age-related macular degeneration (AMD) for which limited treatments exist. The well-studied protein Connexin43 (Cx43) has been shown to be associated with vascular development, permeability and cell death. Our aim was to investigate the therapeutic efficacy of XG19, a Cx43 hemichannel modulating peptide which blocks hemichannel opening in response to injury and specifically targets cell surface expressed Syndecan-4. We therefore investigated the efficacy of XG19 in reducing vascular damage by measuring lesion sizes in fundus images and retinal layer changes in optical coherence tomography (OCT) images in a mouse model of laser-induced CNV.
The in vivo model of CNV relies on laser injury to perforate Bruch's membrane (BM) to induce choroidal blood vessel growth into the retina. Lesions were created with a green argon laser pulse of 532 nm, 50 µm in diameter, and 70 ms duration and 240 mW power. Four lesions were created per eye in six week old, female C57BL/6 mice. After lesions were induced groups of mice received an intraperitoneal injection of XG19 to achieve a final circulating blood concentration of 25 µM (low dose) or 250 µM (high dose) with a control group receiving a saline injection. Lesion progression was observed by fundus and OCT imaging immediately after laser damage on days 0, 1 and 7.
A total of 120 lesions were created in 15 mice. OCT images confirmed that 61 lesions resulted in BM rupture on day 0, with 21 in the saline group, 23 in the low XG19 group and 17 in the high XG19 groups. Lesions with BM rupture formed butterfly lesions on day 1 and thickened outer retinal layers on day 7. Immunohistochemistry confirmed the presence of Syndecan-4 and Cx43 in the lesion areas. High dose XG19 treated mice showed significantly smaller lesion areas compared to saline treated mice on day 7 (p<0.0001).
A single dose of XG19 significantly reduced the overall lesion size over a 7 day period. XG19 therefore has the potential to aid healing mechanisms and reduce vascular leak by blocking Cx43 hemichannel opening. The effect of higher XG19 doses or combination with existing treatments will be explored in future studies.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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