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J.J. Peterson, M. Lukason, A. Scaria, P. Pechan, R. Hillard, Q. Li, R. Miller, S. Boye, S. Wadsworth, W. Hauswirth; Evaluation of a Novel Anti–Neovascular Agent Delivered by an AAV Vector in the Mouse ROP Model . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3222.
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© ARVO (1962-2015); The Authors (2016-present)
Proliferative diabetic retinopathy and the advanced, wet form of age related macular degeneration are characterized by retinal neovascularization (NV) in the inner retina and choroid, respectively. Expression of vascular endothelial growth factor (VEGF) through interactions with its receptors is the best understood stimulus leading to such ocular NV. Our strategy is to block the interactions of VEGF with its receptors. We evaluated efficacy of an AAV vectored anti–neovascular agent in the retinopathy of prematurity (ROP) mouse model.
The cDNA for a novel secretable protein based on the soluble VEGF–receptor (sFlt–1) was inserted into an AAV2 vector and injected into one eye of C57–BL6 neonatal mice at P2. As a negative control, vector expressing a reverse GFP transcript was used. For a positive control, comparison was made with a PEDF expressing vector. Treated pups and controls were subjected to conditions of the ROP model and sacrificed at P17. Vascular nuclei at the inner limiting membrane from every 5th 5–micron section across each eye were enumerated by three masked counters. The average number of neovascular nuclei for each treated eye as a percentage of that found in the untreated eye (%UTE) was compiled.
The sFLT–1 based therapeutic vector gave reduced numbers of nuclei in treated eyes of 16 +/–22 % UTE while the negative control was 81 +/– 50% UTE. Levels for the sFlt vector were comparable to that of mice treated with PEDF vector (27 +/–33 % UTE). Despite sizable variation in the neovascular response of untreated and control litter–mates to the ROP model, therapy was clearly evident, particularly when the NV response to ROP conditions was the most robust.
A potent therapeutic AAV2 vector with a clear mechanism of action based upon a novel secretable form of Flt–1 successfully treats retinal NV in mice subjected to the ROP model. This agent is being further developed in the hope of providing a more suitable long–term alternative than is currently available for the loss of visual function in patients suffering from ocular diseases involving NV.
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