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

Tu, L, Wang, JH, Barathi, VA, Prea, SM, He, Z, Lee, JH, Bender, J, King, AE ORCID: 0000-0003-1792-0965, Logan, GJ, Alexander, IE, Bee, YS, Tai, MH, Dusting, GJ, Bui, BV, Zhong, J and Liu, G ORCID: 0000-0003-3379-724X 2018 , 'AAV-mediated gene delivery of the calreticulin anti-angiogenic domain inhibits ocular neovascularization' , Angiogenesis, vol. 21, no. 1 , pp. 95-109 , doi: 10.1007/s10456-017-9591-4.

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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 Type: Article
Authors/Creators:Tu, L and Wang, JH 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, YS and Tai, MH and Dusting, GJ and Bui, BV and Zhong, J and Liu, G
Keywords: AAV, calreticulin anti-angiogenic domain, diabetic retinopathy, gene therapy, neovascular age-related macular degeneration, ocular neovascularization
Journal or Publication Title: Angiogenesis
Publisher: Springer Netherlands
ISSN: 0969-6970
DOI / ID Number: 10.1007/s10456-017-9591-4
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© Springer Science+Business Media B.V., part of Springer Nature 2018

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