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J Flannery, L McGee-Sanftner, WW Hauswirth; AAV-Vectored Glial Cell Line-Derived Neurotrophic Factor (GDNF) Effects On Photoreceptor Degeneration In Transgenic s334ter Rats . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2893.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We evaluated the efficacy of glial cell-derived neurotrophic factor (GDNF) to slow photoreceptor death in a rat model of autosomal dominant retinitis pigmentosa, expressing a c-terminal truncated rhodopsin (S334ter) Methods: We injected recombinant adeno-associated virus (rAAV), containing the chicken ß-actin promoter-CMV enhancer driving human GDNF cDNA or GFP at P15. Therapeutic effects were assessed by morphometry and ERG analysis at P60. Results: Expression of human recombinant GDNF was detected by Western blotting in retinas transduced with AAV-GDNF, but not from untransduced or AAV-GFP-transduced retinas. Immunohistochemistry localized human GDNF to inner and outer segments of photoreceptor cells and RPE cells. Superior and inferior regions of AAV-GDNF injected rats showed significantly greater ONL thickness in comparison to AAV-GFP-injected or uninjected animals. In the superior hemisphere, AAV-GDNF retinas had a significantly (p<0.05) thicker ONL (23.8+4.1 µm) compared to 16.3+2.5 µm in AAV-GFP controls or 15.4+2.2 µm in uninjected eyes. In the inferior hemisphere, AAV-GDNF retinas had ONL thicknesses of 28.8+2.8µm compared to 21.9+3.0µm in AAV-GFP controls or 21.4+2.6 µm in uninjected (p<0.05). In the superior region, retinas injected with AAV-GDNF retain an ONL with 6-8 rows of photoreceptor nuclei, compared to 4-6 rows in AAV-GFP, and 2-3 rows in uninjected controls at P60. AAV-GDNF injected retinas retain better organized inner and outer segments and significantly increased scotopic ERG relative to contralateral control retinas. At P60, ERGs from S334ter-4 eyes injected with AAV-GDNF showed a statistically significant (p<0.05) retention of a-wave mean amplitude, 74.3+15.5 µm compared to 60.9+11.3 µm in AAV-GFP control or 53.0+9.5 µm in uninjected. AAV-GDNF retinas had increased b-wave mean amplitude, 360.9+50.8 µm compared to 315.5+42.2 µm in AAV-GFP controls or 298.5+33.2 µm in uninjected (p<0.05). Neither neovascularization nor inflammation was observed in eyes injected with AAV-CBA-GDNF. Conclusion: We conclude that AAV-GDNF delivery had a significant rescue effect on photoreceptor degeneration in this animal model without significant side effects.
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