Dual gene therapy with extracellular superoxide dismutase and catalase attenuates experimental optic neuritis.
OBJECTIVE
To ameliorate experimental optic neuritis by combining scavenging of superoxide by germ line increases in the extracellular superoxide dismutase (ECSOD) and hydrogen peroxide by viral-mediated gene transfer of the human catalase gene.


METHODS
The human catalase gene inserted into recombinant adeno-associated virus (rAAV) was injected into the right eyes of transgenic mice overexpressing human ECSOD and wild-type littermates. Animals were simultaneously sensitized for experimental autoimmune encephalomyelitis (EAE) and then sacrificed one month later. The effects of antioxidant genes (ECSOD and catalase) on the histologic lesions of EAE were measured by computerized analysis of myelin area, optic disc area, extent of the cellular infiltrate, cerium derived H(2)O(2) reaction product and extravasation of serum albumin detected by immunogold.


RESULTS
Combined scavenging of H(2)O(2) and superoxide with ECSOD and catalase suppressed demyelination by 72%, 54% due to catalase, and 19% due to ECSOD. Disruption of the blood-brain barrier was reduced 63% by the combined effects of catalase and ECSOD, 35% due to catalase and 29% due to ECSOD.


CONCLUSIONS
Transgene modulation of antioxidant enzyme defenses against both superoxide and its metabolite H(2)O(2) provide a substantial suppressive effect against EAE in the optic nerve that may be a new therapeutic strategy for suppression of optic neuritis and multiple sclerosis.
Qi
Xiaoping
X
Department of Ophthalmology, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
Hauswirth
William W
WW
Guy
John
J
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001812:Blood-Brain Barrier; D002374:Catalase / Q000235:genetics* / Q000378:metabolism; D002452:Cell Count; D000229:Dependovirus / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications; D045604:Extracellular Fluid / Q000201:enzymology*; D016166:Free Radical Scavengers / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology; D009902:Optic Neuritis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010211:Papilledema / Q000209:etiology / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D013481:Superoxides / Q000037:antagonists & inhibitors
D000975:Antioxidants; D016166:Free Radical Scavengers; D013481:Superoxides; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase