Modelling of Antigenomic Therapy of Mitochondrial Diseases by Mitochondrially Addressed RNA Targeting a Pathogenic Point Mutation in mtDNA [RNA]

April 1st, 2014 by Tonin, Y., Heckel, A.-M., Vysokikh, M., Dovydenko, I., Meschaninova, M., Rotig, A., Munnich, A., Venyaminova, A., Tarassov, I., Entelis, N.

Defects in mitochondrial genome can cause a wide range of clinical disorders, mainly neuromuscular diseases. Up to now, no efficient therapeutic treatment has been developed against this class of pathologies. Since most of deleterious mitochondrial mutations are heteroplasmic, meaning that wild type and mutated forms of mtDNA coexists 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. 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.
  • Posted in Journal of Biological Chemistry, Publications
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