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M.S. Ward, A. Khoobehi, E.B. Lavik, A.M. Holdt, A.A. Mwidau, R. Langer, M.J. Young; Biodegradable Microspheres Containing Glial Derived Neurotrophic Factor Encourage Long Term Survival of Retinal Ganglion Cells in the DBA/2J Mouse Glaucoma Model . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1176.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: GDNF has been shown to increase survival of retinal ganglion cells (RGCs) following axotomy–induced short–term degeneration. Biodegradable microspheres allow for slow, more physiological delivery of this neurotrophic factor. Using GDNF containing microspheres, we seek to increase survival of RGCs in glaucoma–like long–term degeneration as observed in the retinae of DBA/2J mice. Methods: Microspheres encapsulating GDNF were formed using the spontaneous emulsification technique. Release studies were performed in vitro in PBS for 60 days and release was quantified using ELISA assays. At 2, 4, 6, and 8 months, DBA/2J mice were injected in ipsilateral eyes with 1µ of concentrated microspheres using a Hamilton syringe. Three sham control groups received either lens injury, corneal injury, or blank polymer injections. For all groups, contralateral eyes served as negative controls. Two months after treatment, RGCs were labeled with 4% Fluorogold solution, a retrograde neural tracer applied to the superior colliculus. 3–5 days post–op, eyes were collected and fixed in 4% Paraformaldehyde for 30 min. Retinas were whole–mounted and RGCs counted in 24 representative high–powered fields at 60x. Results: ELISA assays showed an initial burst of 2–4 ng GDNF per mg of polymer, followed by 20–30 days of no factor release. This period was followed by a 30–day phase of gradual release resulting in the cumulative release of ∼20 ng of GDNF per mg of polymer. Early time points show little significant difference between treated and untreated eyes and RGC density remains relatively constant. At 8 months survival, GDNF treated eyes exhibit 11% more RGCs than untreated controls (p<.05). Lens injury and corneal injury improved survival by 7% (not statistically significant). At 10 months, RGC density in contralateral eyes dropped 61%, but only 21% in GDNF treated eyes. At this time point, treated eyes showed 56% more RGCs than untreated controls (p<.01). Conclusions: Our data from untreated eyes show a rapid period of RGC degeneration between 8 and 12 months. We observed that GDNF releasing microspheres increase RGC survival during this critical period. As such, biodegradable microspheres present a promising means of cell rescue in a glaucoma–like model of degeneration.
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