As a result, there is a dramatic elevation of thymidine and deoxyuridine in blood and tissues (38) and severe deoxynucleotide pool imbalance, which causes multiple mtDNA deletions, depletion, and site-specific point mutations (39). One obvious therapeutic approach is to eliminate the toxic metabolites through hemodialysis, but single treatments had only transient effect in two patients (40) whereas chronic dialysis for over a year failed to slow Inhibitors,research,lifescience,medical disease progression in one patient (41). Nor did prolonged peritoneal dialysis fare any better

(42). Attempts to replace the missing TPase using erythrocyte-encapsulated TPase or platelet infusion did improve symptoms but paradoxically did not lower plasma nucleotide levels (42). Michio Hirano took a more radical approach to Inhibitors,research,lifescience,medical enzyme replacement therapy by employing allogeneic hematopoietic stem cell transplantation (HSCT), which proved very effective in a first patient (43, 44) and has been successful to date in five of the 11 patients so treated (45). An international therapeutic trial is underway and will hopefully confirm that this approach, though risky, can be a lifesaver in MNGIE. In recent years, increasing attention has been directed Inhibitors,research,lifescience,medical to mitochondrial biogenesis and, more specifically, to the peroxisome proliferator-activated

receptor γ coactivator-1α protein (PGC-1α for short), a transcriptional coactivator that binds to several transcription factors Inhibitors,research,lifescience,medical and induces gene expression (46). Importantly, PGC-1α is a strong promoter of mitochondrial biogenesis and function (47). This property has been exploited by French clinical scientists, who used bezafibrate (a PGC-1α activator), an Src inhibitor approved drug in Europe, to treat patients Inhibitors,research,lifescience,medical with imborn errors of fatty acid oxidation (48, 49) and respiratory chain defects (50). In a series of

elegant papers, Tina Wenz and Carlos Moraes in Miami illustrated both the pathogenic role of PGC-1α and its potential therapeutic usefulness. Particularly relevant to the therapy of human mitochondrial myopathies, Non-specific serine/threonine protein kinase they used a knock-in mouse model of mitochondrial myopathy with partial COX deficiency due to a mutation in the assembly gene COX10. Promoting mitochondrial biogenesis either by transgenic expression of PG1-α or by administration of bezafibrate resulted in improved respiratory chain function and ATP production, delayed appearance of the myopathy, and prolonged lifespan (51, 52). There is a form of gene therapy for mtDNA-related diseases that is ready for experimentation in humans but is stalled by ethical concerns. Pathogenic mtDNA mutations, especially those affecting tRNA genes can be eliminated literally ab ovo by transferring an in vitro-fertilized nucleus from the ooplasm of a woman carrying the mutation to an enucleated oocyte from a normal donor.