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Gene Therapy with Single-Subunit Yeast NADH-Ubiquinone Oxidoreductase (NDI1) Improves the Visual Function in Experimental Autoimmune Encephalomyelitis (EAE) Mice Model of Multiple Sclerosis (MS)

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Abstract

Mitochondrial dysfunction mediated loss of respiration, oxidative stress, and loss of cellular homeostasis contributes to the neuronal and axonal degenerations permanent loss of function in experimental autoimmune encephalomyelitis model (EAE) of multiple sclerosis (MS). To address the mitochondrial dysfunction mediated visual loss in EAE mice, self-complementary adeno-associated virus (scAAV) containing the NADH-dehydrogenase type-2 (NDI1) complex I gene was intravitreally injected into the mice after the onset of visual defects. Visual function assessed by pattern electroretinogram (PERGs) showed progressive loss of function in EAE mice were improved significantly in NDI1 gene therapy-treated mice. Serial optical coherence tomography (OCT) revealed that progressive thinning of inner retinal layers in EAE mice was prevented upon NDI1 expression. The 45% optic nerve axonal and 33% retinal ganglion cell (RGC) loss contributed to the permanent loss of visual function in EAE mice were ameliorated by NDI1-mediated prevention of mitochondrial cristae dissolution and improved mitochondrial homeostasis. In conclusion, targeting the dysfunctional complex I using NDI1 gene can be an approach to address axonal and neuronal loss responsible for permanent disability in MS that is unaltered by current disease modifying drugs.

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Acknowledgments

The authors thank Dr. Vittorio Porciatti for his advice on PERG experiments and Dr. William W. Hauswirth’s lab for assistance with AAV viral packaging.

Funding

This work was partially supported by an unrestricted grant to Bascom Palmer Eye institute from Research to Prevent Blindness, NIH core grant no. P30 EY014801.

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  1. Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, 1638 NW 10th Ave, Room#413, Miami, FL, 33136, USA

    Venu Talla, Rajeshwari Koilkonda & John Guy

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  1. Venu Talla
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  2. Rajeshwari Koilkonda
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VT and RDK participated in conducting experiments, acquiring, analyzing, and interpreting data. VT drafted the manuscript with critical review from RDK and JG. JG and VT conceived and supervised the study.

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Correspondence to Venu Talla.

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The authors declare that they have no competing interests.

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The protocol for the study was approved by the University of Miami Institutional Animal Care and Use Committee, and all the procedures were conducted in accordance with the United States Public Health Service’s Policy on Humane Care and Use of Laboratory Animals.

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Talla, V., Koilkonda, R. & Guy, J. Gene Therapy with Single-Subunit Yeast NADH-Ubiquinone Oxidoreductase (NDI1) Improves the Visual Function in Experimental Autoimmune Encephalomyelitis (EAE) Mice Model of Multiple Sclerosis (MS). Mol Neurobiol 57, 1952–1965 (2020). https://doi.org/10.1007/s12035-019-01857-6

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