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Anna M Demetriades, Chendong Pan, Leah C Byrne, Erum Ahmed, Jeffrey Harder, Simon W John, John Gerard Flannery; Müller glial cell-specific GDNF expression promotes retinal ganglion cell survival in DBA/2J mice. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
This study aims to promote retinal ganglion cell survival in a long-term glaucoma model by using a cell-specific AAV vector (ShH10) to express GDNF in Müller glial cells.
3-month old DBA/2J mice received an intravitreal injection (1x1010 vector genomes) of ShH10.GDNF or ShH10.GFP or no treatment. Ocular examinations and eye pressure measurements were performed at bimonthly intervals. Mice were sacrificed at 10.5 months. GDNF ELISA assay was performed on ocular tissues and RGC survival was quantified.
At 10.5 months, untreated eyes had significantly higher eye pressure (21.5±6.0, n=76) compared to ShH10.GDNF treated eyes (18.3±6.8, n=86, p=0.002) and Sh10.GFP eyes (18.3±8.5, n=78, p=0.008). Iris transillumination defects and corneal mineralization was reduced in ShH10.GDNF eyes compared to ShH10.GFP and untreated eyes. GDNF levels were increased in ShH10.GDNF eyes compared to ShH10.GFP eyes and untreated eyes in iris tissue (1974 vs. undetectable), retinal tissue (8184 vs. undetectable and 114) and optic nerve (1111 vs. undetectable) (n=10). ShH10.GDNF eyes showed 2.7 times greater RGC density (1432 ± 69 cells/mm2, n=36) compared to untreated eyes (530 ± 40 cells/mm2, n=32, p<0.0001) and 1.9 times greater RGC density compared to ShH10.GFP eyes (739 ± 44 cells/mm2, n=36, p<0.0001).
Intravitreal ShH10.GDNF results in a reduction in eye pressure and milder anterior segment pigmentary glaucoma findings compared to untreated control eyes in the DBA/2J mouse. Increased expression of GDNF is demonstrated in ocular tissues of ShH10.GDNF treated eyes with improved RGC survival compared to ShH10.GFP and untreated control eyes. These findings suggest that Müller glial cell-specific delivery of GDNF may be a potential therapy for pigmentary glaucoma by targeting a number of mechanisms including pigment dispersion, eye pressure reduction and neuroprotection.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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