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Mutation-free cells prevent transmission of mtDNA disease and enable new treatment options

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Mitochondrial diseases are among the most common inborn errors of metabolism, in at least 15% caused by mitochondrial DNA (mtDNA) mutations. Considering the clinical severity and lack of treatment, preventing transmission to offspring is often requested. Preimplantation Genetic Diagnosis or embryo selection is currently the best reproductive option for most cases of maternally transmitted heteroplasmic mtDNA point mutations. Analysis of PGD embryos demonstrated a role for genetic drift in combination with the mitochondrial bottleneck, but also revealed selection mechanisms. To get further insight in bottleneck and selection mechanisms, we explored zebrafish as a model.  We characterized the mtDNA copy number in germline and non-germline cells in zebrafish throughout development and determined the occurrence of de novo mtDNA mutations, which in humans are responsible for 25% of the mtDNA cases. By knocking-down Tfam we were able to manipulate the mtDNA copy number during zebrafish development. The next step will be the introduction of mtDNA mutations. Due to the high rate of de novo cases, preventing the transmission is not sufficient to eliminate mtDNA disease and it remains essential to develop new therapeutic approaches to treat patients. Currently, we are establishing a treatment based on autologous mtDNA mutation-free muscle stem cell, called mesoangioblasts, which can be administered through the blood to treat myopathy in patients with mtDNA disease. We have approval for starting a phase I/II clinical trial early next year in 5 patients with the m.3243A>G mutation, who by nature produce mutation-free mesoangioblasts. To improve the therapeutic potential of these stem cells, we will stimulate mitochondrial biogenesis and load them with nanoparticles, containing antigenomic compounds, that prohibit replication of the mutated mtDNA in existing muscle fibres.

This talk is part of the MRC Mitochondrial Biology Unit Seminars series.

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