4.6 Article

A Hypoxia-Responsive Glial Cell-Specific Gene Therapy Vector for Targeting Retinal Neovascularization

Journal

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume 55, Issue 12, Pages 8044-8053

Publisher

ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.14-13932

Keywords

hypoxia; GFAP; Muller cell; HIF-1 responsive element; OIR model; gene therapy

Categories

Funding

  1. NIH [EYO16119]
  2. American Heart Association [0815022E]
  3. Neuroscience Research Priority - Florida Atlantic University

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PURPOSE. Muller cells, the major glial cell in the retina, play a significant role in retinal neovascularization in response to tissue hypoxia. We previously designed and tested a vector using a hypoxia-responsive domain and a glial fibrillary acidic protein (GFAP) promoter to drive green fluorescent protein (GFP) expression in Muller cells in the murine model of oxygen-induced retinopathy (OIR). This study compares the efficacy of regulated and unregulated Muller cell delivery of endostatin in preventing neovascularization in the OIR model. METHODS. Endostatin cDNA was cloned into plasmids with hypoxia-regulated GFAP or unregulated GFAP promoters, and packaged into self-complementary adeno-associated virus serotype 2 vectors (scAAV2). Before placement in hyperoxia on postnatal day (P) 7, mice were given intravitreal injections of regulated or unregulated scAAV2, capsid, or PBS. Five days after return to room air, on P17, neovascular and avascular areas, as well as expression of the transgene and vascular endothelial growth factor (VEGF), were compared in OIR animals treated with a vector, capsid, or PBS. RESULTS. The hypoxia-regulated, glial-specific, vector-expressing endostatin reduced neovascularization by 93% and reduced the central vaso-obliteration area by 90%, matching the results with the unregulated GFAP-Endo vector. Retinas treated with the regulated endostatin vector expressed substantial amounts of endostatin protein, and significantly reduced VEGF protein. Endostatin production from the regulated vector was undetectable in retinas with undamaged vasculature. CONCLUSIONS. These findings suggest that the hypoxia-regulated, glial cell-specific vector expressing endostatin may be useful for treatment of neovascularization in proliferative diabetic retinopathy.

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