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Keith R. G. Martin, Harry A. Quigley, Donald J. Zack, Hana Levkovitch-Verbin, Jennifer Kielczewski, Danielle Valenta, Lisa Baumrind, Mary Ellen Pease, Ronald L. Klein, William W. Hauswirth; Gene Therapy with Brain-Derived Neurotrophic Factor As a Protection: Retinal Ganglion Cells in a Rat Glaucoma Model. Invest. Ophthalmol. Vis. Sci. 2003;44(10):4357-4365. doi: 10.1167/iovs.02-1332.
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purpose. To develop a modified adenoassociated viral (AAV) vector capable of efficient transfection of retinal ganglion cells (RGCs) and to test the hypothesis that use of this vector to express brain-derived neurotrophic factor (BDNF) could be protective in experimental glaucoma.
methods. Ninety-three rats received one unilateral, intravitreal injection of either normal saline (n = 30), AAV-BDNF-woodchuck hepatitis posttranscriptional regulatory element (WPRE; n = 30), or AAV-green fluorescent protein (GFP)-WPRE (n = 33). Two weeks later, experimental glaucoma was induced in the injected eye by laser application to the trabecular meshwork. Survival of RGCs was estimated by counting axons in optic nerve cross sections after 4 weeks of glaucoma. Transgene expression was assessed by immunohistochemistry, Western blot analysis, and direct visualization of GFP.
results. The density of GFP-positive cells in retinal wholemounts was 1,828 ± 299 cells/mm2 (72,273 ± 11,814 cells/retina). Exposure to elevated intraocular pressure was similar in all groups. Four weeks after initial laser treatment, axon loss was 52.3% ± 27.1% in the saline-treated group (n = 25) and 52.3% ± 24.2% in the AAV-GFP-WPRE group (n = 30), but only 32.3% ± 23.0% in the AAV-BDNF-WPRE group (n = 27). Survival in AAV-BDNF-WPRE animals increased markedly and the difference was significant compared with those receiving either AAV-GFP-WPRE (P = 0.002, t-test) or saline (P = 0.006, t-test).
conclusions. Overexpression of the BDNF gene protects RGC as estimated by axon counts in a rat glaucoma model, further supporting the potential feasibility of neurotrophic therapy as a complement to the lowering of IOP in the treatment of glaucoma.
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