Modeling of antigenomic therapy of mitochondrial diseases by mitochondrially addressed RNA targeting a pathogenic point mutation in mitochondrial DNA

Tonin, Y.; Heckel, A.; Vysokikh, M.; Dovydenko, I.; Meschaninova, M.; Rötig, A.; Munnich, A.; Venyaminova, A.; Tarassov, I.; Entelis, N.

Авторы: Tonin Yann, Heckel Anne-Marie, Vysokikh Mikhail, Dovydenko Ilya, Meschaninova Mariya, Rötig Agnès, Munnich Arnold, Venyaminova Alya, Tarassov Ivan, Entelis Nina
Журнал: The Journal of biological chemistry
Том: 289
Номер: 19
Год издания: 2014
Первая страница: 13323
Последняя страница: 13334
DOI: 10.1074/jbc.M113.528968
Аннотация: 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.
Добавил в систему: Высоких Михаил Юрьевич

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Modeling of antigenomic therapy of mitochondrial diseases by mitochondrially addressed RNA targeting a pathogenic point mutation in mitochondrial DNAстатья

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