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

journal contribution
posted on 2023-05-19, 15:19 authored by Tu, L, Wang, J-H, Barathi, VA, Prea, SM, He, Z, Lee, JH, James BenderJames Bender, Anna KingAnna King, Logan, GJ, Alexander, IE, Bee, Y-S, Tai, M-H, Dusting, GJ, Bui, BV, Zhong, J, Guei-Sheung LiuGuei-Sheung Liu
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.

History

Publication title

Angiogenesis

Volume

21

Pagination

95-109

ISSN

0969-6970

Department/School

Wicking Dementia Research Education Centre

Publisher

Springer Netherlands

Place of publication

Netherlands

Rights statement

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

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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