Assess the mtDNA Mutation Load in Mesoangioblasts of mtDNA Mutation Carriers

Rationale: Mitochondrial diseases caused by defects in oxidative phosphorylation (OXPHOS) due to heteroplasmic mitochondrial DNA (mtDNA) mutations are rare (frequency 1/5,000), but severe multi-system disorders. Clinical manifestations are highly variable, but predominantly affect energy demanding tissues, like brain and muscle. Myopathy is a common feature of mtDNA disorders, being present in more than 50% of the mtDNA mutation carriers, and seriously affects patients' general well-being and quality of life. Currently, no treatment is available for these patients, although the induction of muscle regeneration by exercise treatment has been shown to alleviate their myopathy. This implies that these patients can produce muscle fibres that perform better, most likely because the mutation load is lower. Mesoangioblasts (MABs) are myogenic precursors that have been recognized as a source for development of a systemic myogenic stem-cell therapy, and allogeneic transplantation has been successfully applied to mice and dogs with Duchenne muscular dystrophy. A subsequent phase I/II clinical study in boys with DMD demonstrated that donor MABs treatment was relatively safe, but did not result in clinical improvement, which can partly be attributed to the required use of immunosuppressive agents. The use of autologous MABs would circumvent this and a previous study of our group demonstrated that this is feasible for half of the mtDNA mutation carriers of 6 different mtDNA mutations, as their mtDNA mutation load in mesoangioblasts was (nearly) absent (<10%). However, there are many more mtDNA mutations in the 16.5kb mtDNA and the aim of this study is to determine the mtDNA mutation load in mesoangioblasts of other mtDNA mutation carriers and identify the patients or mutations for which this is a feasible approach.