title: Modeling of antigenomic therapy of mitochondrial diseases by mitochondrially addressed RNA targeting a pathogenic point mutation in mitochondrial DNA.
abstract: Defects in mitochondrial genome can cause a wide range of clinical disorders, mainly neuromuscular diseases. Presently, no efficient therapeutic treatment has been developed against this class of pathologies. Because most of deleterious mitochondrial mutations are heteroplasmic, meaning that wild type and mutated forms of mitochondrial DNA (mtDNA) coexist in the same cell, the shift in proportion between mutant and wild type molecules could restore mitochondrial functions. Recently, we developed mitochondrial RNA vectors that can be used to address anti-replicative oligoribonucleotides into human mitochondria and thus impact heteroplasmy level in cells bearing a large deletion in mtDNA. Here, we show that this strategy can be also applied to point mutations in mtDNA. We demonstrate that specifically designed RNA molecules containing structural determinants for mitochondrial import and 20-nucleotide sequence corresponding to the mutated region of mtDNA, are able to anneal selectively to the mutated mitochondrial genomes. After being imported into mitochondria of living human cells in culture, these RNA induced a decrease of the proportion of mtDNA molecules bearing a pathogenic point mutation in the mtDNA ND5 gene.
authors.affiliation: From the UMR 7156 Génétique Moléculaire, Génomique, Microbiologie (GMGM), Strasbourg University-CNRS, Strasbourg 67084, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Tonin
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Heckel
authors.forename: Mikhail
authors.initials: M
authors.lastname: Vysokikh
authors.forename: Ilya
authors.initials: I
authors.lastname: Dovydenko
authors.forename: Mariya
authors.initials: M
authors.lastname: Meschaninova
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Alya
authors.initials: A
authors.lastname: Venyaminova
authors.forename: Ivan
authors.initials: I
authors.lastname: Tarassov
authors.forename: Nina
authors.initials: N
authors.lastname: Entelis
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D000077278:RNA, Mitochondrial; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D000077278:RNA, Mitochondrial; D012313:RNA; C481838:MT-ND5 protein, human; D042967:Electron Transport Complex I
keywords: Cybrid Cells; Fibroblast; Heteroplasmy; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Transport; RNA Transport; RNA-based Therapeutics; Respiratory Chain