Concise Review: Induced Pluripotent Stem Cell‐Based Drug Discovery for Mitochondrial Disease

High attrition rates and loss of capital plague the drug discovery process. This is particularly evident for mitochondrial disease that typically involves neurological manifestations and is caused by nuclear or mitochondrial DNA defects. This group of heterogeneous disorders is difficult to target because of the variability of the symptoms among individual patients and the lack of viable modeling systems. The use of induced pluripotent stem cells (iPSCs) might significantly improve the search for effective therapies for mitochondrial disease. iPSCs can be used to generate patient‐specific neural cell models in which innovative compounds can be identified or validated. Here we discuss the promises and challenges of iPSC‐based drug discovery for mitochondrial disease with a specific focus on neurological conditions. We anticipate that a proper use of the potent iPSC technology will provide critical support for the development of innovative therapies against these untreatable and detrimental disorders. Stem Cells 2017;35:1655–1662 Once induced pluripotent stem cells (iPSCs) have been derived from mitochondrial patients, isogenic controls can be generated using genome editing technologies. Correcting the mutations is, however, currently very challenging in the case of mtDNA. The choice of an effective neural cell model is critical for enabling the establishment of high‐throughput compound screenings. The screenings can be developed based on targets that are already known or on cellular phenotypes that are identified using the iPSC‐derived neural cells. After the screenings, several validation steps using various methods and model systems are necessary before being able to propose any compound as a treatment, leading to a personalized strategy for drug discovery of neurological mitochondrial disease.