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Wenjun Xiong, Alexandra MacColl Garfinkel, Yiqing Li, Larry Benowitz, Connie L Cepko; Nrf2 promotes neuron survival in mouse models of neurodegeneration and acute nerve damage. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3188.
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© ARVO (1962-2015); The Authors (2016-present)
Oxidative damage accompanies many types of pathologic conditions, as well as normal aging. Attempts have been made to combat oxidation, primarily in the form of small molecules, in animal models and in clinical trials, but these approaches have not been successful. Our goal was to develop a more targeted and sustained approach to combat oxidative damage, using gene therapy and the genes that normally combat oxidation and stress.
We created several AAV vectors (serotype 8) that encode genes that combat oxidation. One set of vectors encodes SOD2 and catalase, which directly reduce ROS. Another set encodes one of two transcription factors, Nrf2 and PGC1a, which regulate hundreds of genes that combat oxidative stress. We tested these vectors in 3 mouse models of retinal degeneration and a nerve crush model.
In all models, we were able to promote the survival of the neurons. Interestingly, Nrf2 was the most effective while the other transcription factor, PGC1a, was actually deleterious to cones. In addition to promoting photoreceptor survival in models of retinitis pigementosa, Nrf2 preserved the outer segments, which are the structures that are crucial for phototransduction. Visual function also was preserved, as demonstrated by electroretinogram and behavioral tests. Finally, these vectors were shown to greatly reduce the ROS load as well as reduce the level of oxidized lipids. In addition to the beneficial effects on photoreceptors, Nrf2 promotes the survival of projection neurons, retinal ganglion cells (RGCs), in an acute nerve crush model.
As far as we know, our study is the first that compares different antioxidant gene therapy strategies, and compares them across in vivo models. Moreover, it is the first direct indication that an upstream antioxidant therapy using a transcription factor is more effective than the delivery of antioxidant enzymes. The fact that survival was promoted in both photoreceptor cells and RGCs suggests that these vectors may be broadly applicable, in such diseases as age-related macular degeneration, where oxidation is clearly established, as well as for diseases outside the eye, including Parkinson’s disease, Alzheimer’s disease and Amyotrophic lateral sclerosis.
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