SIRT1 and NRF2 Gene Transfer Mediate Distinct Neuroprotective Effects Upon Retinal Ganglion Cell Survival and Function in Experimental Optic Neuritis

Investigative Ophthalmology & Visual Science
Devin S McDougaldKenneth S Shindler

Abstract

Optic neuritis is a condition defined by autoimmune-mediated demyelination of the optic nerve and death of retinal ganglion cells. SIRT1 and NRF2 stimulate anti-inflammatory mechanisms and have previously demonstrated therapeutic value in preclinical models of neurodegenerative disease. Here we investigated the neuroprotective potential of SIRT1 or NRF2 gene transfer using adeno-associated virus (AAV) vectors in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. C57Bl/6J mice were administered intravitreal doses of AAV2 vectors and immunized to induce EAE symptoms. Visual function was examined by recording the optokinetic response (OKR) just prior to EAE induction and once every 7 days postinduction for 7 weeks. Retina and optic nerves were harvested to investigate retinal ganglion cell survival (immunolabeling with Brn3a antibodies); inflammation (hematoxylin and eosin staining); and demyelination (luxol fast blue staining). Animals modeling EAE demonstrate reduced visual acuity compared to sham-induced controls. Intravitreal delivery of AAV2-NRF2 did not preserve visual function. However, AAV2-SIRT1 mediated significant preservation of the OKR compared to AAV2-eGFP controls. Treatment with AAV2-N...Continue Reading

Citations

Jan 30, 2019·Current Opinion in Neurology·Michael DietrichPhilipp Albrecht
Apr 11, 2020·Oxidative Medicine and Cellular Longevity·Ming-Xuan WangYa-Juan Zheng
Nov 3, 2020·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Paula I Fuller-CarterLivia S Carvalho
Aug 23, 2019·Biochemical and Biophysical Research Communications·Jun MaQin Sun
Dec 8, 2020·Cellular and Molecular Bioengineering·Wei SongYu-Bo Fan
Jan 14, 2021·International Journal of Molecular Sciences·Ewa Maria KratzAgnieszka Piwowar
May 10, 2020·Molecular Therapy. Methods & Clinical Development·Junkai TanNing Fan
May 19, 2021·Translational Vision Science & Technology·Ying Kai ChanUNKNOWN Ocular Gene Therapy Inflammation Working Group

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Methods Mentioned

BETA
transgenic
PCR
dissection

Software Mentioned

ImageJ
GraphPad Prism
GraphPad

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