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Wei Liu, Yonju Ha, Shuang Zhu, Hua Liu, Nisha Azhar, Julia E. Gerson, Massoud Motamedi, Rakez Kayed, Wenbo Zhang; AAV2-GRP78-mediated gene therapy prevents retinal neuronal injury via downregulation of Tau oligomers. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1752. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ganglion cell (RGC) death following axonal injury that occurs in traumatic optic neuropathy or glaucoma causes irreversible vision loss. Currently, there is no proven effective therapy to prevent RGC death in such conditions. This study aims to determine whether RGC can be protected from death by eliminating endoplasmic reticulum (ER) stress with adeno-associated virus (AAV)-mediated gene therapy and to investigate the mechanisms underlying its beneficial effects
Optic nerve crush (ONC) model was used to study RGC death after axonal injury, in which the optic nerve was crushed 2 mm behind the eye globe. Infection efficiency and location of different AAV serotypes in mice retinas were tested in vivo using green fluorescent protein as a marker after intravitreal injection. AAV2 was selected to introduce GRP78 gene into the retina. ER stress signaling molecules, tau oligomers and RGC injury were examined by immunohistochemistry or Western blot
Among AAV1, 2, 5, 6, 8 and 9, AAV2 was the most efficient serotype that infects and delivers genes to RGCs. At 3 days after ONC, there was a marked increase in ER stress and RGC apoptosis. GRP78 is a molecular chaperon that enhances protein folding and controls the activation of ER stress pathways. GRP78 overexpression not only attenuated ER stress but also reduced RGC apoptosis by 64.4% (n=5, p<0.05). At 7 days after ONC, there was 58.8% RGC loss in mice receiving intravitreal AAV2-null and such loss was reduced to 35.7% in mice receiving AAV2-GRP78 (n=5, p<0.05). RGC function, as indicated by the positive scotopic threshold responses of electroretinography, was prominently reduced at 7 days after ONC, which was significantly prevented by AAV2-GRP78. Since protein aggregation is increased during ER stress and aggregated proteins such as tau oligomers are key players in neurodegenerative diseases, we examined tau oligomers in the retina and found that AAV2-GRP78 alleviated ONC-induced increase in tau oligomers. Blocking tau oligomers with a novel tau oligomer monoclonal antibody (TOMA) significantly attenuated ONC-induced RGC loss.
These data indicate that gene therapy with AAV2-GRP78 or immunotherapy with TOMA offer novel therapeutic approaches to prevent RGC loss after axonal injury. The effect of AAV2-GRP78 is partially mediated by the reduction of tau oligomer formation
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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