Using a hypoxia-responsive domain together with a glia fibrillary acidic protein (GFAP) cell–specific promoter to maintain glial cell specificity,
Janet Blanks and her colleagues1 tested the hypothesis that this novel combination of elements in an adeno-associated virus (AAV) vector construct expressing endostatin is as effective in reducing neovascularization in an oxygen-induced retinopathy model as gene therapy with constitutively expressed endostatin. As proof of principle, they specifically targeted the major Müller glial cells because these retinal cells navigate across the retina and respond to hypoxic stress following capillary loss in diabetes and normally express vascular endothelial growth factor (VEGF) in this model.
Their previous work selectively targeted endostatin with an RPE-targeted gene therapy for choroidal neovascularization.
2 To suppress ocular neovascularization, endostatin was selected in this new model for its known effects on angiogenesis affecting more than VEGF-dependent pathways.
3 Endostatin, a cleavage product of collagen XVIII, inhibits endothelial cell proliferation, migration, and survival. In addition, it increases expression of antiangiogenic factors while inhibiting proangiogenic factors, such as ephrins and hypoxia-inducible factors. Endostatin blocks VEGF-induced microvascular permeability by rapidly stabilizing occludin and tight junctions. Following internalization into endothelial cells, endostatin localizes to the nucleus to reduce VEGF expression and increase pigment epithelium-derived factor (PEDF) expression.
The important hallmark of this current work is based on combining and creating a glial cell–specific inducible endostatin for gene therapy that may be applicable to potential combinations of targeted treatment strategies, including macular degeneration, to suppress leakage and growth of choroidal neovascularization.
3,4 More importantly, these current studies lay the groundwork for, and possibly extend, clinical studies to be used for prophylactic gene therapy for diabetic patients who are at a higher risk for retinal neovascularization and visual loss.