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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    • "While animal models have been crucial in the investigation of disease mechanisms, fundamental developmental, biochemical and physiological differences exist between animals and humans. The importance of utilizing human cells for these purposes is evident by the large number of drugs that show efficacy and safety in rodent models of diseases but subsequently fail in human clinical trials, which are partly attributed to these species differences (Rubin, 2008). Furthermore, the overwhelming majority of neurological disease is of a sporadic nature, rendering animal modeling ineffective , while it is unclear whether the relatively rare monogenic forms of disease truly represent the vast majority of sporadic cases. "
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    ABSTRACT: The groundbreaking technologies of induced pluripotency and lineage conversion have generated a genuine opportunity to address fundamental aspects of the diseases that affect the nervous system. These approaches have granted us unrestricted access to the brain and spinal cord of patients and have allowed for the study of disease in the context of human cells, expressing physiological levels of proteins and under each patient's unique genetic constellation. Along with this unprecedented opportunity have come significant challenges, particularly in relation to patient variability, experimental design and data interpretation. Nevertheless, significant progress has been achieved over the past few years both in our ability to create the various neural subtypes that comprise the nervous system and in our efforts to develop cellular models of disease that recapitulate clinical findings identified in patients. In this Review, we present tables listing the various human neural cell types that can be generated and the neurological disease modeling studies that have been reported, describe the current state of the field, highlight important breakthroughs and discuss the next steps and future challenges.
    The EMBO Journal 04/2015; 34(11). DOI:10.15252/embj.201591267 · 10.43 Impact Factor
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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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