Stem Cells and Drug Discovery: The Beginning of a New Era?

Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge MA 02138, USA.
Cell (Impact Factor: 32.24). 03/2008; 132(4):549-52. DOI: 10.1016/j.cell.2008.02.010
Source: PubMed


Much of the attention focused on stem cells relates to their use in cell replacement therapy; however, stem cells may also transform the way in which therapeutics are discovered and validated.

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    • "The recommendations outlined for evaluating differentiated stem cell phenotypes were developed specifically to address patient safety concerns such as tumorigenicity and immunologic incompatibility , due to the initial focus of the industry on regenerative-medicine applications (Fink, 2009). Concerns about patient safety may have slowed the commercialization of regenerative therapies (Fox, 2011), but the use of industrial stem cell-based products for in vitro research, particularly pharmaceutical screening applications (Placzek et al., 2009; Rubin, 2008; Thomson, 2007; Wobus and Löser, 2011), is a promising goal that can potentially be reached in the near term. Due to the mandate to test all drug compounds for potential adverse effects on the heart, in vitro cardiac toxicity screening is a particularly important application that has prompted the development of commercial stem cell-derived cardiac myocytes by a number of companies (Webb, 2009). "
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    ABSTRACT: Advances in stem cell manufacturing methods have made it possible to produce stem cell-derived cardiac myocytes at industrial scales for in vitro muscle physiology research purposes. Although FDA-mandated quality assurance metrics address safety issues in the manufacture of stem cell-based products, no standardized guidelines currently exist for the evaluation of stem cell-derived myocyte functionality. As a result, it is unclear whether the various stem cell-derived myocyte cell lines on the market perform similarly, or whether any of them accurately recapitulate the characteristics of native cardiac myocytes. We propose a multiparametric quality assessment rubric in which genetic, structural, electrophysiological, and contractile measurements are coupled with comparison against values for these measurements that are representative of the ventricular myocyte phenotype. We demonstrated this procedure using commercially available, mass-produced murine embryonic stem cell- and induced pluripotent stem cell-derived myocytes compared with a neonatal mouse ventricular myocyte target phenotype in coupled in vitro assays.
    Stem Cell Reports 03/2014; 2(3):282-94. DOI:10.1016/j.stemcr.2014.01.015 · 5.37 Impact Factor
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    • "The attrition rate of drugs in development for humans, much of which can be attributed to unforeseen toxic side effects, mainly cardiotoxicity and hepatotoxicity48 that were not observed in preclinical animal models, is a significant problem facing the pharmaceutical industry. Approximately 30% of the medicines that have entered clinical trials were abandoned because of a lack of efficacy and another 30% were halted because of safety concerns49. "
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    ABSTRACT: The revolutionary induced pluripotent stem cell (iPSC) technology provides a new path for cell replacement therapies and drug screening. Patient-specific iPSCs and subsequent differentiated cells manifesting disease phenotypes will finally position human disease pathology at the core of drug discovery. Cells used to test the toxic effects of drugs can also be generated from normal iPSCs and provide a much more accurate and cost-effective system than many animal models. Here, we highlight the recent progress in iPSC-based cell therapy, disease modeling and drug evaluations. In addition, we discuss the use of small molecule drugs to improve the generation of iPSCs and understand the reprogramming mechanism. It is foreseeable that the interplay between iPSC technology and small molecule compounds will push forward the applications of iPSC-based therapy and screening systems in the real world and eventually revolutionize the methods used to treat diseases.
    Acta Pharmacologica Sinica 04/2013; 34(6). DOI:10.1038/aps.2013.21 · 2.91 Impact Factor
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    • "Induced pluripotent stem cells (iPSCs) hold an enormous potential for biomedical research (e.g. regenerative medicine, drug discovery) (Rubin, 2008; Xu et al., 2008; Deng, 2010) and current stem cell research pursues the generation of iPSCs in an efficient and safe manner. Since the original report of Takahashi and Yamanaka (2006), different strategies with the aim at replacing the viral transduction of exogenous transcription factors by small molecules, proteins, mRNA or microRNA have been described (Feng et al., 2009; Kim et al., 2009; Judson et al., 2009; Warren et al., 2010). "
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    ABSTRACT: Current strategies to monitor reprogramming into induced pluripotent stem cells (iPSCs) are limited in that they rely on the recognition of advanced stage biomarkers or they involve the transduction of genetically-modified cells. These limitations are particularly problematic in high-throughput screenings where cell availability, low cost and a rapid experimental protocol are critical issues. Herein we report the application of a pluripotent stem cell fluorescent probe (i.e. CDy1) as a reporter for the rapid screening of chemicals in reprogramming iPSCs. CDy1 stains early-stage iPSCs at 7dpi as well as matured iPSCs; hence it can partially overcome the slow kinetics of the reprogramming process. As a proof of concept, we employed a CDy1-based screening in 384 well-plates to examine the effect of newly synthesized hydroxamic acid derivatives in reprogramming mouse fibroblasts transduced with Oct4, Sox2 and Klf-4 without c-Myc. One compound (1-26) was identified as a reprogramming enhancer by 2.5-fold and we confirmed that 1-26 behaves as a histone deacetylase (HDAC) inhibitor. The successful identification of novel small molecules enhancing the generation of iPSCs by means of a rapid and simple protocol demonstrates the suitability of this CDy1-based screening platform for the large scale and high-throughput evaluation of iPSC modulators.
    Stem Cell Research 06/2012; 9(3):185-191. DOI:10.1016/j.scr.2012.06.006 · 3.69 Impact Factor
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