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K.C. Leonard, D. Petrin, S.G. Coupland, A.N. Baker, B.C. Leonard, R.G. Korneluk, C. Tsilfidis; XIAP (X–Linked Inhibitor of Apoptosis) Gene Therapy Protects Photoreceptors in Animal Models of Retinitis Pigmentosa (RP) . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4693.
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Purpose: XIAP inhibits apoptosis by blocking the action of caspases 3, 7 and 9. The current study assessed XIAP rescue of photoreceptors in transgenic rat models of RP. Methods: The P23H and S334ter transgenic models of RP were used to test the neuroprotective effects of XIAP gene therapy. Recombinant adeno–associated virus (AAV) encoding either XIAP or green fluorescent protein (GFP; injection control) was injected subretinally into one eye of heterozygous transgenic rat pups at approximately postnatal day 16. The contralateral eye served as an uninjected control. Electroretinograms (ERGs) were recorded at biweekly intervals for up to 32 weeks post–injection. Eyes were examined at various timepoints using histology and immunohistochemistry. Results: Western analysis confirmed the over–expression of XIAP in virus–injected eyes. Significant structural protection of the photoreceptors was evident in the XIAP–injected eye by 16 weeks post–injection in both the P23H and S334ter lines. No preservation of photoreceptor morphology was found in the contralateral uninjected eye, or the GFP–injected control eyes. Immunohistochemistry confirmed the co–localization of XIAP transgene expression with the area showing structural protection. ERG analysis showed preservation of photoreceptor function in the XIAP–treated eye in comparison to both uninjected and GFP–injected control eyes. Conclusions: AAV–mediated delivery of XIAP to the photoreceptor cells seems to provide both structural and functional protection in two models of retinal degeneration. This gene therapy strategy holds great promise for the treatment of RP, as it allows for the broad protection of photoreceptors, regardless of the initial disease causing mutation. The long time course and progressive nature of RP implies that even if intervention is implemented after diagnosis, there is still hope the XIAP will significantly delay, if not completely halt the disease progression.
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