Inhibition of Retinal Neovascularization by Intraocular Viral-Mediated Delivery of Anti-angiogenic Agents

Abstract

Neovascularization characterizes diabetic retinopathy and choroidal neovascularization associated with age-related macular degeneration, the most common causes of severe visual loss in the developed world. Gene transfer to the eye using adeno-associated viral (AAV) vectors is a promising new treatment for inherited and acquired ocular diseases. We used an AAV vector with rapid onset and high levels of gene expression in the retina to deliver three anti-angiogenic factors (pigment epithelium-derived factor, tissue inhibitor of metalloproteinase-3, and endostatin) to the eyes of mice in a mouse model of retinopathy of prematurity. All three vectors inhibited ischemia-induced neovascularization.

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

“…62 Similar promising results were obtained in the same mouse model of retinopathy of prematurity, using rAAV-2/1-carrying genes encoding for endostatin, tissue inhibitor of metalloproteinase-3 (TIMP-3) or PEDF. 63 For choroidal neovascularization (CNV), an rAAV-2/ 2pedf was intravitreally or subretinally injected in mice where the Bruch's membrane was ruptured with laser photocoagulation, a mice model of induced neovascularization. At 4-6 weeks after intraocular injection of rAAV2pedf, the area of CNV at the Bruch's membrane rupture sites had significantly decreased compared with the CNV area at rupture sites in eyes injected with rAAV-2/ 2gfp.…”

In vivo adenovirus-mediated delivery of a uPA/uPAR antagonist reduces retinal neovascularization in a mouse model of retinopathy

“…The angiostatic activities of ATF and endostatin have already been described in numerous tumor models. 10,11,13,15 This is the first time that AFT has been shown to have angiostatic activity in a model of retinal neovascularization. We showed that that local gene transfer and the expression of ATFHSA reduce retinal neovascularization by 78.1%.…”

“…In other studies, the inhibition of neovascularization by endostatin was of the same order (80%). 15 However, endostatin reduces angiogenesis by inhibiting different steps of the angiogenic process, such as endothelial cell proliferation, apoptosis and cell migration in response to VEGF. 21 In this model of retinal vascularization, VEGF plays a key role, as its expression is regulated during hyperoxia (downregulation) and hypoxia (upregulation).…”

“…12 Endostatin, the C-terminal fragment of collagen XVIII, inhibits tumor growth 13,14 and ocular angiogenesis 15,16 in an endothelial cell-specific manner. 17,18 In this study, we used a replication-deficient adenovirus vector carrying the mATF or the endostatin gene coupled to human serum albumin (HSA) to improve the half-life of the therapeutic protein in the circulation.…”

AAV-mediated gene therapy for retinal disorders: from mouse to man

“…Neovascularization can be inhibited by adenovirus-mediated or rAAV-mediated expression of vascular endothelial growth factor inhibitors, such as the soluble vascular endothelial growth factor receptor (sFlt-1), [91][92][93] angiostatin 94 or endostatin. 95 The size of laser-induced choroidal neovascularization lesions can also be reduced by a zinc-finger transcription factor that upregulates PEDF expression when delivered by AAV2. 96 Adenovirus-mediated overexpression of PEDF inhibits retinal and choroidal neovascularization, and furthermore, is reported to induce regression of established new vessels.…”