title: Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction.
abstract: Mitochondrial diseases due to mutations in mitochondrial DNA can no longer be ignored in most medical areas. With prevalence certainly higher than one in 6000, they probably represent the most common form of metabolic disorders. Despite progress in identification of their molecular mechanisms, little has been done with regard to therapy. We have recently optimized the allotopic expression for the mitochondrial genes ATP6, ND1, and ND4 and obtained a complete and long-lasting rescue of mitochondrial dysfunction in the human fibroblasts in which these genes were mutated. However, biosafety and benefit to mitochondrial function must be validated in animal models prior to clinical applications. To create an animal model of Leber Hereditary Optic Neuropathy (LHON), we introduced the human ND4 gene harboring the G11778A mutation, responsible of 60% of LHON cases, to rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells (RGCs), which were 40% less abundant in treated eyes than in control eyes. This deleterious effect was also confirmed in primary cell culture, in which both RGC survival and neurite outgrowth were compromised. Importantly, RGC loss was clearly associated with a decline in visual performance. A subsequent electroporation with wild-type ND4 prevented both RGC loss and the impairment of visual function. Hence, these data provide the proof-of-principle that optimized allotopic expression can be an effective treatment for LHON, and they open the way to clinical studies on other devastating mitochondrial disorders.
authors.affiliation: Institut de la Vision, Université Pierre et Marie Curie-Paris6, Unité mixte de recherche S 592, 17 rue Moreau, Paris F-75012, France.
authors.forename: Sami
authors.initials: S
authors.lastname: Ellouze
authors.forename: Sébastien
authors.initials: S
authors.lastname: Augustin
authors.forename: Aicha
authors.initials: A
authors.lastname: Bouaita
authors.forename: Crystel
authors.initials: C
authors.lastname: Bonnet
authors.forename: Manuel
authors.initials: M
authors.lastname: Simonutti
authors.forename: Valérie
authors.initials: V
authors.lastname: Forster
authors.forename: Serge
authors.initials: S
authors.lastname: Picaud
authors.forename: Jose-Alain
authors.initials: JA
authors.lastname: Sahel
authors.forename: Marisol
authors.initials: M
authors.lastname: Corral-Debrinski
mesh_terms: D000818:Animals; D001766:Blindness / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009154:Mutation; D009245:NADH Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase
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