Study and Treatment of Mitochondrial DNA Depletion Syndrome 3 Using iPSCs

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Project Summary We have previously described a procedure that allows us to efficiently differentiate cells with hepatocyte characteristics from human induced pluripotent stem cells. We have also shown that iPSCs derived from patients with inborn errors of hepatic metabolism can be used to model metabolic liver disease in culture. Here we propose to use this approach to study a rare disease called Mitochondrial DNA Depletion Syndrome 3 (Hepatocerebral type) (MTDPS3) that is caused by mutations in the Deoxyguanine Kinase (DGUOK) gene. We propose to generate iPSC-derived hepatocytes that contain different mutations in DGUOK and compare the effect of these mutations on mtDNA copy number, mitochondrial activity, and hepatocyte function. Finally, we propose to use these cells as a platform to identify drugs that can be used to treat MTDPS3 and potentially other mitochondrial DNA depletion syndromes.