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Chad E. Bigelow, Stephen Poor, Yubin Qiu, Shawn M. Hanks, Michael Maker, Elizabeth Fassbender, Siyuan Shen, Amber Woolfenden, Bruce D. Jaffee; Development of a Rabbit Model to Assess Anti-Angiogenic Therapies that Modulate Human VEGF-Mediated Retinal Vessel Pathology. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1384.
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To develop a large eye, non-primate model of VEGF-induced pathology for assessing anti-VEGF therapies.
A range of intravitreally delivered VEGF doses (200-500 ng/eye human VEGF165) were given to Dutch Belted rabbits to select the optimal dose. Effects of repeated VEGF doses were assessed with periodic injections for up to 12 weeks. Inhibition of retinal vessel pathology was quantified 4 days after administration of ranibizumab (500 ug/eye) vs. vehicle control.Two complementary, noninvasive imaging methods were developed to assess retinal vessel pathology. One quantified changes in vessel diameter by scanning laser ophthalmoscope (SLO) images of vessels with i.v. FITC-labeled dextran in conjunction with optical coherence tomography (OCT). A complementary technique quantified vessel leakage 3 min. after i.v. fluorescein injection. Subtraction of the normalized and aligned FITC-dextran and fluorescein leakage images yielded the contribution of extravasated dye.
Retinal vessels responded to intravitreally injected VEGF consistently and repeatedly at an optimal dose of 400 ng. Lower doses induced milder pathology, while higher doses did not extend the range of measurable abnormalities. 48 hours post-VEGF injection, significant fluorescein leakage occurred concomitant with a 2-fold increase in vessel diameter by both FITC-dextran SLO images and OCT. Both abnormalities reverted to near normal 14 days after injection and were repeatedly induced for at least 5 cycles over 12 weeks. Ranibizumab completely inhibited both fluorescein leakage and vascular dilation.
The retinal vasculature in the rabbit responds reproducibly to human VEGF165 in a manner that can be quantified with two complementary imaging modalities. This model offers a number of advantages. First, the model relies on human VEGF, so it can be used to study compounds without requiring non-human primates. Second, the ability to repeatedly test rabbits greatly reduces the number of animals required. Finally, the relatively large rabbit eye is amenable to testing clinical delivery devices.
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