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J. Yao, G. Grahek, L. Jia, N. Khan, W. W. Hauswirth, D. A. Thompson, D. N. Zacks; XIAP Protection of Photoreceptors in the Retinal Degeneration 10 (rd10) Mutant Mouse. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3134.
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To evaluate the neuroprotective effects of AAV delivery of X-linked inhibitor of apoptosis (XIAP) in rd10 mouse, a rodent model caused by a loss-of-function mutation of the β-subunit of rod cGMP phosphodiesterase gene (Pde6b).
The host rd10 mice were born and kept in a dark environment. One eye of the host was subretinally injected with 1ul AAV-XIAP(AAV5-CBA-XIAP-wPRE) or AAV-GFP(AAV5-UF11) at the age of postnatal day (P) 4 or 3 weeks. The contralateral eye was not injected. The animals were maintained for 4 weeks in the dark before they were moved to 12-hour light / 12-hour dark cycling light environment. Histology, immunohistochemistry and ERG were performed at different stages up to 3 weeks after moving to the cycling light environment.
Retinas treated with AAV- XIAP showed structural preservation of the outer nuclear layer (ONL) and outer segments (OS) up to 3 weeks after transfer to the light, whereas AAV-GFP injected eyes and untreated eyes showed severe degeneration after transfer to the light. Immunohistochemistry showed rhodopsin production in the XIAP treaded retinas. ERG analysis, however, did not show functional improvement during the time period of the experiment.
The results suggest that XIAP confers structural protection of photoreceptors in rd10 mice for at least 3 weeks after moving to the cycling light environment. Thus, the delivery of XIAP as an initial treatment may extend the window of opportunity for secondary intervention with targeted gene-replacement therapy. Future work is needed to define the factors involved in the apparent dissociation between preservation of structure versus function.
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