Induced pluripotent stem cells — opportunities for disease modelling and drug discovery

• Published in: Nature reviews. Drug discovery Vol. 10; no. 12; pp. 915 - 929
• Main Authors: Grskovic, Marica, Javaherian, Ashkan, Strulovici, Berta, Daley, George Q.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2011; Nature Publishing Group
• Subjects: 631/136/1425; 631/154; 631/532/2064/2158; Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Cells, Cultured; Disease Models, Animal; Drug Discovery - methods; Drug Discovery - trends; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - pathology; Medicinal Chemistry; Molecular Medicine; Nervous System Diseases - drug therapy; Nervous System Diseases - pathology; Pharmacology/Toxicology; review-article
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/nrd3577

Key Points Induced pluripotent stem cells (iPSCs) that are derived from patients and differentiated in vitro can provide disease-relevant cell types for drug screening. Directed differentiation of iPSCs has yielded many disease-relevant cells — chiefly neurons, hepatocytes, blood cells and cardiomyocytes — but often the cells reflect embryonic stages of development, and may not faithfully reflect disease phenotypes of adult tissues. Methods for deriving iPSCs are evolving, and much remains to be learned about the genetic and epigenetic stability of iPSCs and their relationships to embryonic stem cells, and how this affects the fidelity of drug screening. Notwithstanding a few exceptions, disease modelling so far has focused on Mendelian disorders of high clinical penetrance and with a recognized cellular pathophysiology, such as spinal muscular atrophy, familial dysautonomia, Rett syndrome, Hutchinson–Gilford progeria syndrome and long QT syndrome. Whether more complex, sporadically occurring disease entities can be modelled with iPSCs remains uncertain. Cell-based assays enable the discovery of novel pathways and the identification of compounds with favourable cell permeability and toxicity profiles, but such assays are less amenable to defining the structure–activity relationships that are important for optimizing drug properties. iPSCs offer important advantages for drug toxicity screening against relevant human cells and tissues, and may facilitate the development of ' in vitro clinical trials' to test the efficacy of drugs or gene correction vectors against various distinct patient genotypes. Induced pluripotent stem cells (iPSCs) – whereby a patient's somatic cells are reprogrammed into an embryonic pluripotent state by the forced expression of a defined set of transcription factors – have the potential to transform drug discovery and development. In this article, Daley and colleagues discuss recent advances and current challenges associated with the generation and use of iPSCs. The ability to generate induced pluripotent stem cells (iPSCs) from patients, and an increasingly refined capacity to differentiate these iPSCs into disease-relevant cell types, promises a new paradigm in drug development — one that positions human disease pathophysiology at the core of preclinical drug discovery. Disease models derived from iPSCs that manifest cellular disease phenotypes have been established for several monogenic diseases, but iPSCs can likewise be used for phenotype-based drug screens in complex diseases for which the underlying genetic mechanism is unknown. Here, we highlight recent advances as well as limitations in the use of iPSC technology for modelling a 'disease in a dish' and for testing compounds against human disease phenotypes in vitro . We discuss how iPSCs are being exploited to illuminate disease pathophysiology, identify novel drug targets and enhance the probability of clinical success of new drugs.