SOD2 gene transfer protects against optic neuropathy induced by deficiency of complex I.
Mutations in genes encoding the NADH ubiquinone oxidoreductase, complex I of the respiratory chain, cause a diverse group of diseases. They include Leber hereditary optic neuropathy, Leigh syndrome, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. There is no effective treatment for these or any other mitochondrial disorder. Using a unique animal model of severe complex I deficiency induced by ribozymes targeted against a critical complex I subunit gene (NDUFA1), we attempted rescue of the optic nerve degeneration associated with Leber hereditary optic neuropathy. We used adenoassociated virus to deliver the human gene for SOD2 to the visual system of disease-induced mice. Relative to mock infection, SOD2 reduced apoptosis of retinal ganglion cells and degeneration of optic nerve fibers, the hallmarks of this disease. Rescue of this animal model supports a critical role for oxidative injury in disorders with complex I deficiency and shows that a respiratory deficit may be effectively treated in mammals, thus offering hope to patients.
Department of Ophthalmology, University of Florida, College of Medicine, Gainesville, FL 32610-0284, USA.
Xiaoping
X
Qi
Alfred S
AS
Lewin
Liang
L
Sun
William W
WW
Hauswirth
John
J
Guy
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015152:Blotting, Northern / Q000379:methods; D002452:Cell Count / Q000379:methods; D000229:Dependovirus / Q000378:metabolism; D004195:Disease Models, Animal; D042967:Electron Transport Complex I; D004996:Ethidium / Q000031:analogs & derivatives*; D005452:Fluoresceins; D007839:Functional Laterality; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron / Q000379:methods; D009245:NADH Dehydrogenase; D041681:NIH 3T3 Cells; D009900:Optic Nerve / Q000473:pathology / Q000648:ultrastructure / Q000821:virology; D009901:Optic Nerve Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy; D016337:RNA, Catalytic / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000473:pathology / Q000821:virology; D013482:Superoxide Dismutase / Q000235:genetics / Q000627:therapeutic use*; D000099156:Superoxide Dismutase 2
D042967:Electron Transport Complex I; D004996:Ethidium; D005452:Fluoresceins; D008565:Membrane Proteins; D009245:NADH Dehydrogenase; D016337:RNA, Catalytic; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C492251:Ndufa1 protein, mammalian; C067883:dihydroethidium; C029569:diacetyldichlorofluorescein; C118736:NDUFA1 protein, human; C492250:Ndufa1 protein, mouse