title: Cell therapy using retinal progenitor cells shows therapeutic effect in a chemically-induced rotenone mouse model of Leber hereditary optic neuropathy.
abstract: Primary mitochondrial disorders occur at a prevalence of one in 10 000; ∼50% of these demonstrate ocular pathology. Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial disorder. LHON results from retinal ganglion cell pathology, which leads to optic nerve degeneration and blindness. Over 95% of cases result from one of the three common mutations in mitochondrial genes MTND1, MTND4 and MTND6, which encode elements of the complex I respiratory chain. Various therapies for LHON are in development, for example, intravitreal injection of adeno-associated virus carrying either the yeast NDI1 gene or a specific subunit of mammalian Complex I have shown visual improvement in animal models. Given the course of LHON, it is likely that in many cases prompt administration may be necessary before widespread cell death. An alternative approach for therapy may be the use of stem cells to protect visual function; this has been evaluated by us in a rotenone-induced model of LHON. Freshly dissected embryonic retinal cells do not integrate into the ganglion cell layer (GCL), unlike similarly obtained photoreceptor precursors. However, cultured retinal progenitor cells can integrate in close proximity to the GCL, and act to preserve retinal function as assessed by manganese-enhanced magnetic resonance imaging, optokinetic responses and ganglion cell counts. Cell therapies for LHON therefore represent a promising therapeutic approach, and may be of particular utility in treating more advanced disease.
authors.affiliation: Ocular Genetics Unit, Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Mansergh
authors.affiliation: Ocular Genetics Unit, Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Naomi
authors.initials: N
authors.lastname: Chadderton
authors.affiliation: 1] Ocular Genetics Unit, Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland [2] Research Foundation, The Royal Victoria Eye and Ear Hospital, Dublin, Ireland.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Kenna
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: Oliviero L
authors.initials: OL
authors.lastname: Gobbo
authors.affiliation: Ocular Genetics Unit, Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
authors.forename: G Jane
authors.initials: GJ
authors.lastname: Farrar
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D005819:Genetic Markers; D008279:Magnetic Resonance Imaging; D051379:Mice; D008928:Mitochondria / Q000235:genetics; D009154:Mutation; D029242:Optic Atrophy, Hereditary, Leber / Q000139:chemically induced / Q000235:genetics* / Q000628:therapy*; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology; D012160:Retina / Q000166:cytology*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D012402:Rotenone / Q000633:toxicity*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*
chemical_list: D005819:Genetic Markers; C493237:Ndi1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D012402:Rotenone; D042967:Electron Transport Complex I