Human stem cells were once viewed primarily as regenerative materials for tissue repair through cell therapies. However, advances in technologies and protocols mean that induced pluripotent stem cells (iPSCs) are now playing an increasingly important role in disease modelling and human cell-based screening assays. This roundtable explores what this means for drug discovery.
The pharmaceutical industry’s current issue with attrition in the R&D pipeline is complex and multifaceted. However, few would disagree that one of the biggest factors contributing to the poor rate of success in drug discovery is the lack of reliable and translationally useful disease models.
No matter how carefully studies are designed, animal models and immortalised cell lines cannot reflect the full complexity of human biology and disease mechanisms. While the use of human primary cells or human tissue samples is an attractive alternative for drug screening, these materials can be difficult to obtain, and require additional ethical considerations.
A more physiologically-relevant approach to the preclinical evaluation of drug efficacy and toxicity is the use of stem cells. Stem cells have the unique capacity for indefinite self-renewal and the capability to differentiate into multiple cell types. Pluripotent stem cells (PSCs) can differentiate into most cell types of the body, while tissue-specific stem cells, such as hematopoietic stem cells (HSCs), can differentiate into all mature cell types for a given tissue.
Human iPSCs possess a number of important properties that make them an excellent source of cells for disease models and compound screening assays. Not only do they have the potential to generate the full range of human cell types, they can be derived from any individual, even a patient.
Consequently, patient samples can be used to create iPSC lines that harbour disease-causing mutations, which can subsequently be genetically modified to correct the mutation and study the disease in more detail, or to correct the cells for the development of novel cellular therapies. iPSCs generated from healthy donors can also be genetically modified to introduce disease-causing mutations to validate specific targets in the pathogenesis of a disease.
Furthermore, iPSCs can be expanded to large quantities 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, particularly 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 models (1). 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 limited,” says Dr Gregor von Levetzow, Global Product Manager at Miltenyi Biotec. “Being able to generate 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.".....
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