Abstract
Preclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected by these pathologies. In contrast, only minor progresses have been achieved so far in the translation into the clinics. Many challenges are still ahead, including the need for a better characterization of the pharmacological effects of the different approaches and the design of appropriate clinical trials with robust outcome measures for this extremely heterogeneous, rare, and complex group of disorders. In this review, we will discuss the most important achievements and the major challenges in this very dynamic research field.
Highlights
The extreme genetic, biochemical, and clinical complexity of primary mitochondrial diseases challenges both clinical and research activity in the field
It should be noted that pre-existing liver disease, as occasionally observed in mitochondrial neuro-gastro-intestinal encephalo-myopathy (MNGIE) [57] and other diseases, may prevent the use of associated viral vectors (AAVs) as cellular damage may interfere with viral entry into the cells
The introduction of Transcription activator-like effector nucleases (TALEN) and zinc fingers nucleases (ZFN) made a major step forward towards this end. Both mitochondrial targeted TALENs and mtZFNs were shown to be rather effective in shifting the heteroplasmy of several cellular models with mutations in mitochondrial DNA (mtDNA) [66,67,68]
Summary
The extreme genetic, biochemical, and clinical complexity of primary mitochondrial diseases challenges both clinical and research activity in the field. Mutations in any of the mitochondrial genes encoding the 13 core subunits of the respiratory chain complexes and the 22 mitochondrial tRNAs and two rRNAs, as well as in any of the nuclear genes encoding the rest of the ∼1500 proteins constituting the mitochondrial proteome, may potentially lead to a mitochondrial dysfunction and disease These orders can be transmitted with any kind of inheritance (recessive, dominant, X-linked, and mitochondrial) and can be characterized by multisystemic or organ-specific dysfunction that can arise at any time in life. This tremendous heterogeneity, together with a limited information on the natural history of the disease and a general lack of appropriate models, prevented, so far, the development of effective therapies. The idea of using rapamycin, a widely used mTORC1 inhibitor, to treat mitochondrial diseases stemmed from the observation that inhibiting cytosolic translation significantly prolonged (approximately from 15 to 27 days) the replicative lifespan (i.e. the number of daughter cells a yeast cell can generate before exiting the cell cycle) of mitochondrial mutants in Saccharomyces cerevisiae [8]
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