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Antioxidant gene delivery protects photoreceptors

The inherited form of blindness retinitis pigmentosa (RP) results from a progressive loss of photoreceptors. RP-associated mutations directly promote the death of rod cells, which are required for vision in low light, and indirectly promote the subsequent degeneration of cone cells, which are necessary for daytime vision. While the mechanisms that mediate cone death are not fully understood, an increase in oxidative stress has been implicated in the degradation of these cells. In this episode, Connie Cepko and Wenjun Xiong detail their work, which shows that adeno-associated virus-mediated delivery of antioxidant genes prolongs photoreceptor survival and improves visual acuity in multiple murine RP models. The results of this study suggest that targeted delivery of antioxidant genes has potential to ameliorate other diseases characterized by oxidative stress-induced cell degradation.

Published March 23, 2015, by The JCI

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Related articles

NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage
Wenjun Xiong, … , Larry I. Benowitz, Constance L. Cepko
Wenjun Xiong, … , Larry I. Benowitz, Constance L. Cepko
Published March 23, 2015
Citation Information: J Clin Invest. 2015;125(4):1433-1445. https://doi.org/10.1172/JCI79735.
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Research Article Genetics Neuroscience Ophthalmology

NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

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Abstract

Oxidative stress contributes to the loss of neurons in many disease conditions as well as during normal aging; however, small-molecule agents that reduce oxidation have not been successful in preventing neurodegeneration. Moreover, even if an efficacious systemic reduction of reactive oxygen and/or nitrogen species (ROS/NOS) could be achieved, detrimental side effects are likely, as these molecules regulate normal physiological processes. A more effective and targeted approach might be to augment the endogenous antioxidant defense mechanism only in the cells that suffer from oxidation. Here, we created several adeno-associated virus (AAV) vectors to deliver genes that combat oxidation. These vectors encode the transcription factors NRF2 and/or PGC1a, which regulate hundreds of genes that combat oxidation and other forms of stress, or enzymes such as superoxide dismutase 2 (SOD2) and catalase, which directly detoxify ROS. We tested the effectiveness of this approach in 3 models of photoreceptor degeneration and in a nerve crush model. AAV-mediated delivery of NRF2 was more effective than SOD2 and catalase, while expression of PGC1a accelerated photoreceptor death. Since the NRF2-mediated neuroprotective effects extended to photoreceptors and retinal ganglion cells, which are 2 very different types of neurons, these results suggest that this targeted approach may be broadly applicable to many diseases in which cells suffer from oxidative damage.

Authors

Wenjun Xiong, Alexandra E. MacColl Garfinkel, Yiqing Li, Larry I. Benowitz, Constance L. Cepko

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