Stem Cells


Furthermore, iPSCs can be expanded to large quan- tities and cryopreserved, and can be derived from easily accessible cell types, such as peripheral blood mononuclear cells or skin fibroblasts. This ability to create customised, physiologically


relevant models with relative ease opens up a wealth of new opportunities in drug discovery, par- ticularly for disease areas where access to reliable cell models has historically been a stumbling block. These include neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease, as well as certain cardiac abnormalities, which can be extremely difficult to detect using traditional mod- els1. Therefore having complementary assays based on stem cell-derived cell lines would be an incredibly useful and cost-effective tool for drug discovery efforts. “The availability of primary human brain or


heart tissue for drug discovery purposes is limit- ed,” says Dr Gregor von Levetzow, Global Product Manager at Miltenyi Biotec. “Being able to gener- ate iPSC-derived neurons and cardiomyocytes allows for large-scale drug screening, providing a more precise prediction of drug efficacy in humans than could be achieved with animal experiments alone.”


From tissue repair to disease models and drug screening The use of iPSCs has grown significantly over the past several years with large numbers of pharma- ceutical companies adopting stem cells for toxicity testing and drug screening. However, this wasn’t always the case, and this progress has been made possible in large part due to rapid advances in associated technologies2. Human stem cells were traditionally viewed as


regenerative materials and largely limited to tissue repair applications. A lack of standardised culture and differentiation protocols prevented their use in translational settings, while time-consuming gene editing techniques of the past slowed down the development of stem cell-based disease models. Over the last decade, stem cell maintenance and


differentiation protocols have become much less complex. Culture techniques have now become substantially easier to use, leading to increased scale-up options for high-throughput drug discov- ery settings. Additionally, faster, more efficient and more reproducible gene editing technologies such as CRISPR-Cas9 have redefined what is possible when it comes to designing cell models of disease. Specific disease-associated mutations can now be more easily studied in vitro, enabling analysis of gene function and the underlying role in disease


46


progression. These advances, alongside the enor- mous contributions to iPSC research made by Shinya Yamanaka and James Thomson’s laborato- ries, have rapidly changed the stem cell field3,4. Today, reprogramming donor-provided somatic


cells has become commonplace. The ease with which these cells can be derived from donors, both with and without disease-causing mutations, offers a very attractive way to study the genetic impact of many diseases. Human iPSCs can now be used to produce an almost unlimited number of cells criti- cal for preclinical safety tests. These cells can be generated from cohorts of both healthy and patient donors with diverse genetic backgrounds, to pro- vide a platform for toxicity screening. This makes them more representative of populations, and therefore a more translatable model. What’s more, whole genome sequencing can be


performed on donor lines to identify specific muta- tions that are relevant to a disease. In this way, it is possible to combine clinical presentation with genomic information to create a model that essen- tially mimics a disease in a dish. These models allow researchers to assess how specific demo- graphics and cell types react to novel drugs prior to any clinical tests, preventing drug failures much earlier in the discovery and development process, and thereby helping to reduce costs and improve success rates. With the industry striving for more translational


disease models, a particular focus is being put on 3D cell models. These models, grown in more physiologically-relevant conditions, have the potential to generate more pertinent preclinical insights that can be used to predict efficacy and toxicity. “There’s mounting data to show that liver cells


derived from stem cells grown in 3D are a much better model by which to assess metabolic liabili- ty,” says Dr Richard Eglen, Vice President and General Manager at Corning Life Sciences. “This ability to perform preclinical optimisation of com- pounds before they go into the patient is making a big impact. You can take precise genetic mutations from individual patient populations, and really mimic the action of your compounds in phenotyp- ically-derived cells and get precise measurement of their liability towards metabolism and toxicity.” As recognition of the robustness and translation-


al relevance of 3D stem cell-derived models grows, their use is set to have a particularly important impact on drug discovery research for applications where human cells and tissues act and behave dif- ferently to animal cells and tissues. The observance of more predictive behaviour with iPSCs – when


Drug Discovery World Fall 2018


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