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Published on: March 30, 2020
Vascular targeting of ocular neovascularization with a vascular endothelial growth factor121/gelonin chimeric protein
Hideo Akiyama1, Khalid A Mohamedali, Raquel Lima E Silva
1Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Abstract:
Tumors provide an extremely abnormal microenvironment that stimulates neovascularization from surrounding vessels and causes altered gene expression within vascular cells. Up-regulation of vascular endothelial growth factor (VEGF) receptors has allowed selective destruction of tumor vessels by administration of a chimeric protein consisting of VEGF121 coupled to the toxin gelonin (VEGF/rGel). We sought to determine whether there is sufficient up-regulation of VEGF receptors in endothelial cells participating in ocular neovascularization to permit a similar strategy. After intravenous injection of 45 mg/kg VEGF/rGel, but not uncoupled recombinant gelonin (rGel), there was immunofluorescent staining for rGel within choroidal neovascularization in mice and regression of the neovascularization occurred, demonstrating successful vascular targeting via the systemic circulation. Intraocular injection of 5 ng of VEGF/rGel also caused significant regression of choroidal neovascularization and regression of retinal neovascularization in two models, transgenic mice with expression of VEGF in photoreceptors and mice with ischemic retinopathy, whereas injection of 5 ng of rGel had no effect. These data suggest that the strategy of vascular targeting can be applied to nonmalignant neovascular diseases and could serve as the basis of a new treatment to reduce established ocular neovascularization.
Insights
Targeting vascular endothelial growth factor (VEGF) receptors with a VEGF-toxin fusion protein effectively reduced ocular neovascularization in mouse models. This strategy shows promise for treating nonmalignant neovascular diseases.
Area of Science:
- Ophthalmology
- Vascular Biology
- Oncology
Background:
- Tumors create abnormal microenvironments promoting neovascularization and altered gene expression in vascular cells.
- Vascular endothelial growth factor (VEGF) receptor upregulation enables targeted destruction of tumor vessels using VEGF-toxin conjugates.
- The potential for similar vascular targeting in nonmalignant ocular neovascularization requires investigation.
Purpose of the Study:
- To determine if VEGF receptors are sufficiently upregulated in ocular neovascularization for targeted therapy.
- To evaluate the efficacy of a VEGF-toxin fusion protein (VEGF/rGel) in treating ocular neovascularization models.
Main Methods:
- Systemic and intraocular administration of VEGF/rGel and control (rGel) in mouse models of ocular neovascularization.
- Immunofluorescence staining to detect targeted toxin delivery.
- Assessment of neovascularization regression.
Main Results:
- Intravenous VEGF/rGel administration led to targeted toxin localization and regression of choroidal neovascularization in mice.
- Intraocular VEGF/rGel injection significantly reduced both choroidal and retinal neovascularization in two distinct models.
- Control rGel showed no effect, confirming the specificity of VEGF/rGel's action.
Conclusions:
- Vascular targeting strategies using VEGF-toxin fusion proteins are effective against nonmalignant ocular neovascularization.
- This approach offers a potential new treatment for established ocular neovascular diseases.
- VEGF/rGel demonstrates successful vascular targeting in nonmalignant conditions.
