title: Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model.
abstract: BACKGROUND
  Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder with point mutations in mitochondrial DNA which result in loss of vision in young adults. The majority of mutations reported to date are within the genes encoding the subunits of the mitochondrial NADH-quinone oxidoreductase, complex I. Establishment of animal models of LHON should help elucidate mechanism of the disease and could be utilized for possible development of therapeutic strategies.
  
  
  RESULTS
  We established a rat model which involves injection of rotenone-loaded microspheres into the optic layer of the rat superior colliculus. The animals exhibited the most common features of LHON. Visual loss was observed within 2 weeks of rotenone administration with no apparent effect on retinal ganglion cells. Death of retinal ganglion cells occurred at a later stage. Using our rat model, we investigated the effect of the yeast alternative NADH dehydrogenase, Ndi1. We were able to achieve efficient expression of the Ndi1 protein in the mitochondria of all regions of retinal ganglion cells and axons by delivering the NDI1 gene into the optical layer of the superior colliculus. Remarkably, even after the vision of the rats was severely impaired, treatment of the animals with the NDI1 gene led to a complete restoration of the vision to the normal level. Control groups that received either empty vector or the GFP gene had no effects.
  
  
  CONCLUSIONS
  The present study reports successful manifestation of LHON-like symptoms in rats and demonstrates the potential of the NDI1 gene therapy on mitochondrial optic neuropathies. Our results indicate a window of opportunity for the gene therapy to be applied successfully after the onset of the disease symptoms.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Marella
authors.forename: Byoung Boo
authors.initials: BB
authors.lastname: Seo
authors.forename: Biju B
authors.initials: BB
authors.lastname: Thomas
authors.forename: Akemi
authors.initials: A
authors.lastname: Matsuno-Yagi
authors.forename: Takao
authors.initials: T
authors.lastname: Yagi
mesh_terms: D000818:Animals; D002460:Cell Line; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D029242:Optic Atrophy, Hereditary, Leber / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012402:Rotenone / Q000633:toxicity; D015003:Yeasts / Q000201:enzymology*
chemical_list: D012402:Rotenone; D009245:NADH Dehydrogenase