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 advent of hiPSC technology [1] has provided an opportunity to revolutionise modern medicine. Aside from their potential use in the cell therapy sector as clinical grade raw material to produce treatments for a variety of disorders with unmet clinical needs, hiPSCs also offer a more near term application as a tool with which current drug discovery, phenotypic screens, and safety testing programmes might be qualitatively improved [2] [3] [4] [5]. "
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    ABSTRACT: This paper describes a decisional tool that is designed to identify cost-effective process designs for drug screening products derived from human induced pluripotent stem cells (hiPSC). The decisional tool comprises a bioprocess economics model linked to a search algorithm to assess the financial impact of manual and automated bioprocessing strategies that use 2D-planar tissue culture technologies. The tool was applied to a case study that examines the production of patient-specific iPSC-derived neurons for drug screening. The production strategies were compared across three analytical drug screening methods, each requiring cell production at a distinct scale (manual patch-clamp analysis, high throughput screening and plate-based pharmacology), as well as different annual cell line utilization requirements (‘throughputs’) (between 10-100 lines) so as to represent different industry scenarios. The tool determined the critical cell line throughput where the most cost-effective production strategy switched from the manual to automated workflow. The key process economics driver was the number of iPSC expansion stages required. Stochastic modelling of the bioprocess illustrated that the automated was more robust than the manual workflow in the scenarios investigated. The tool predicted the level of performance improvements required in iPSC expansion and differentiation as well as reductions in indirect costs and media costs so as to achieve an acceptable cost of goods (COG).
    Full-text · Article · Oct 2015 · Biochemical Engineering Journal
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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.
    Full-text · Article · Apr 2015 · The EMBO Journal
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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.
    Full-text · Article · Mar 2014 · Stem Cell Reports
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