iPSC-Based Drug Discovery of Neurological Mitochondrial DNA Diseases

Background: Mutations in mitochondrial DNA (mtDNA)cause diseases typically affecting the nervous system and forwhich no effective treatment exists. It has been difficult to developanimal models of mitochondrial diseases due to challengesof engineering mtDNA. Existing cellular models lackthe metabolic features of neural cells and do not provide thepatient-specific match between mitochondrial and nuclear genomes.Here, we propose to establish a novel system to carryour drug discovery experiments.Materials and Methods: We generated neural progenitor cells(NPCs) from human induced pluripotent stem cells (iPSCs) andanalyzed their genetic and metabolic properties. We also obtainedNPCs from iPSCs derived from patients carrying pathogenicmtDNA mutations.Results: We show that neural cells derived from human iPSCsdisplay the correct functional and bioenergetics properties toinvestigate the neurological impairment associated with mitochondrialdisorders. We used patient iPSC-derived neural cellscarrying mutations in mtDNA genes to carry out a proof-ofprinciplehigh-throughput compound screening using FDA-approvedcompounds. We identify drugs that have the potential tobe repositioned in the context of mtDNA diseases.Conclusion: Patient iPSC-derived NPCs represent an effectivemodel system in which carry out compound screenings. Ourdata pave the way to the identification of disease-modifyingtherapies for currently untreatable mtDNA disorders.