Modeling of Antigenomic Therapy of Mitochondrial Diseases by Mitochondrially Addressed RNA Targeting a Pathogenic Point Mutation in Mitochondrial DNA*
| Autor: | Anne-Marie Heckel, Ilya S. Dovydenko, Agnès Rötig, Yann Tonin, Ivan Tarassov, Mikhail Y. Vysokikh, Arnold Munnich, Alya G. Venyaminova, Mariya I. Meschaninova, Nina Entelis |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Mitochondrial DNA Mitochondrial Diseases Adolescent RNA Mitochondrial macromolecular substances Biology MT-RNR1 Biochemistry Human mitochondrial genetics DNA Mitochondrial Cell Line Mitochondrial Proteins Humans Point Mutation Molecular Biology Mitochondrial transport Sequence Deletion Genetics Homoplasmy Electron Transport Complex I Base Sequence musculoskeletal neural and ocular physiology Cell Biology Genetic Therapy Heteroplasmy mitochondrial fusion nervous system DNAJA3 RNA |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|