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AAV-mediated gene delivery of the calreticulin anti-angiogenic domain inhibits ocular neovascularization

Citation

Tu, L and Wang, J-H and Barathi, VA and Prea, SM and He, Z and Lee, JH and Bender, J and King, AE and Logan, GJ and Alexander, IE and Bee, Y-S and Tai, M-H and Dusting, GJ and Bui, BV and Zhong, J and Liu, G-S, AAV-mediated gene delivery of the calreticulin anti-angiogenic domain inhibits ocular neovascularization, Angiogenesis, 21, (1) pp. 95-109. ISSN 0969-6970 (2018) [Refereed Article]

Copyright Statement

Springer Science+Business Media B.V., part of Springer Nature 2018

DOI: doi:10.1007/s10456-017-9591-4

Abstract

Ocular neovascularization is a common pathological feature in diabetic retinopathy and neovascular age-related macular degeneration that can lead to severe vision loss. We evaluated the therapeutic efficacy of a novel endogenous inhibitor of angiogenesis, the calreticulin anti-angiogenic domain (CAD180), and its functional 112-residue fragment, CAD-like peptide 112 (CAD112), delivered using a self-complementary adeno-associated virus serotype 2 (scAAV2) in rodent models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. The expression of CAD180 and CAD112 was elevated in human umbilical vein endothelial cells transduced with scAAV2-CAD180 or scAAV2-CAD112, respectively, and both inhibited angiogenic activity in vitro. Intravitreal gene delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly inhibited ischemia-induced retinal neovascularization in rat eyes (CAD180: 52.7% reduction; CAD112: 49.2% reduction) compared to scAAV2-mCherry, as measured in retinal flatmounts stained with isolectin B4. Moreover, the retinal structure and function were unaffected by scAAV2-CAD180 or scAAV2-CAD112, as measured by optical coherence tomography and electroretinography. Moreover, subretinal delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly attenuated laser-induced choroidal neovascularization in mouse eyes compared to scAAV2-mCherry, as measured by fundus fluorescein angiography (CAD180: 62.4% reduction; CAD112: 57.5% reduction) and choroidal flatmounts (CAD180: 40.21% reduction; CAD112: 43.03% reduction). Gene delivery using scAAV2-CAD180 or scAAV2-CAD112 has significant potential as a therapeutic option for the management of ocular neovascularization.

Item Details

Item Type:Refereed Article
Keywords:AAV, calreticulin anti-angiogenic domain, diabetic retinopathy, gene therapy, neovascular age-related macular degeneration, ocular neovascularization
Research Division:Technology
Research Group:Medical Biotechnology
Research Field:Gene and Molecular Therapy
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Inherited Diseases (incl. Gene Therapy)
UTAS Author:Bender, J (Mr James Bender)
UTAS Author:King, AE (Associate Professor Anna King)
UTAS Author:Liu, G-S (Dr Guei-Sheung Liu)
ID Code:123851
Year Published:2018
Web of Science® Times Cited:2
Deposited By:Menzies Institute for Medical Research
Deposited On:2018-01-30
Last Modified:2019-02-18
Downloads:0

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