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Anna M Demetriades, Chendong Pan, Leah Byrne, Jeffrey Harder, Simon W John, John Gerard Flannery; AAV mediated delivery of NT4 specifically to Müller glial cells promotes retinal ganglion cell survival in the DBA/2J mouse model of glaucoma.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6135.
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© ARVO (1962-2015); The Authors (2016-present)
This study examined the efficacy of using a cell-specific AAV vector (ShH10) to express Neurotophin-4 (NT4) in Müller glial cells as a method of promoting retinal ganglion cell survival in a long-term model of glaucoma.
3-month old DBA/2J mice received either an intravitreal injection (1x1010 vector genomes) of ShH10.NT4, an ShH10.GFP control or no injection. Ocular examinations and eye pressure measurements were performed at bimonthly intervals. Mice were sacrificed at 10.5 months. NT4 ELISA assay was performed on ocular tissues and RGC survival was quantified.
At 10.5 months, untreated eyes had significantly higher eye pressure (23.5±6.9, n=162) compared to ShH10.NT4 treated eyes (19.8±8, n=168, p=0.001) and Sh10.GFP eyes (18.3±8.5, n=168, p=0.008). ShH10.NT4 eyes had less iris transillumination defects compared to ShH10.GFP and untreated eyes. NT4 levels (pg/mg total protein) were increased in ShH10.NT4 eyes compared to ShH10.GFP eyes and untreated eyes in iris tissue (1904 vs. 29 and 25), retinal tissue (1627 vs. 178 and 437) and optic nerve (252 vs. undetectable and 122) (n=5). ShH10.NT4 eyes showed 2.6 times greater RGC density (1361 ± 51 cells/mm2, n=56) compared to untreated eyes (531 ± 39 cells/mm2, n=32, p<0.0001) and 2.3 times greater RGC density compared to ShH10.GFP eyes (594 ± 40 cells/mm2, n=60, p<0.0001).
Intravitreal ShH10.NT4 results in a reduction in eye pressure and milder anterior segment findings compared to untreated control eyes in the DBA/2J mouse. Increased expression of NT4 is demonstrated in ocular tissues of ShH10.NT4 treated eyes with improved RGC survival compared to ShH10.GFP and untreated control eyes. These findings suggest that Müller glial cell-specific delivery of NT4 may hold promise as a potential therapy for glaucoma by promoting retinal ganglion cell survival.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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