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

Abstract

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 patientspecific 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 SIGNIFICANCE STATEMENTMitochondrial disease is an untreatable condition caused by mutations in nuclear or mitochondrial DNA. This review describes the application of patient-derived induced pluripotent stem cells (iPSCs) in the drug discovery process of mitochondrial disease. iPSCs allow the development of innovative and effective cellular model systems in a personalized approach. Their use may significantly benefit the search for treatments against debilitating mitochondrial disease.

Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects

“…Because of the above, we plan to test the rescuing activity of the β32_33 peptide on specialized and differentiated cells and organoids, such as minibrains, 24,25 which are increasingly been developed from induced pluripotent stem cells (hiPSCs) reprogrammed from primary patient‐derived cell cultures 26‐28 …”

Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile

“…Unlike in iNs, each iPSC line is a clonal derivative of one single fibroblast. Due to the fact that iPSC reprogramming and expansion are highly selective processes, the generation of heteroplasmic iPSC lines from mtDNA disease patients allows comparison of “mutation-rich” to “mutation-free” iPSC lines from the same donor (Fujikura et al, 2012; Inak et al, 2017). While this is a clear advantage for iPSCs when it comes to the investigation of a certain mtDNA mutation, such model iPSC lines do not necessarily reflect the genetic state in a patient’s cells (Folmes et al, 2013; Hatakeyama et al, 2015; Hämäläinen et al, 2013).…”

Using stem cell–derived neurons in drug screening for neurological diseases

“…The advent of these different differentiation protocols has facilitated research on many neurological diseases using iPSCs. The current state of this research has been recently reviewed for a range of diseases (Gibbs et al, 2018;Inak et al, 2017;McKinney, 2017;Poon et al, 2017;Tamburini and Li, 2017) including Parkinson's disease (Cobb et al, 2018;Singh Dolt et al, 2017), Alzheimer's disease (Arber et al, 2017;Robbins and Price, 2017), amytrophic lateral sclerosis and frontotemporal dementia (Guo et al, 2017;Preza et al, 2016), Huntington's disease (Tousley and Kegel-Gleason, 2016), childhood neurological diseases (Barral and Kurian, 2016;Santos and Tiscornia, 2017), and psychiatric disorders (Adegbola et al, 2017;Watmuff et al, 2017). These reviews cover differentiation of specific neuronal subtypes and relevant disease phenotypes observed in these cells, therefore these topics will not be covered here.…”