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Benefits & Key Considerations of Using Human iPSC-Derived Disease Models in Drug Discovery

The process of drug discovery, development and commercialisation is long and associated with high costs. In addition, it is estimated that only 1% of the initially tested compounds make it to the market. Noelia Muñoz-Martín and Elena Matsa at Ncardia describe how human iPSC-derived disease models improve drug discovery and what the main challenges and solutions are for the successful generation and application of these models.

Extract:

Benefits & Key Considerations of Using Human iPSC-Derived Disease Models in Drug Discovery

The process of drug discovery, development and commercialisation is long and associated with high costs. In addition, it is estimated that only 1% of the initially tested compounds make it to the market. To decrease this high attrition rate, it is necessary to implement physiologically relevant disease models with higher predictability much earlier in of drug discovery. Disease models based on human induced pluripotent stem cell (iPSC) technology has the potential to revolutionise drug discovery. These models recapitulate, in vitro, many clinical features of human pathology and can be used for phenotypic screening with clinically relevant readouts. This article describes how human iPSC-derived disease models can improve drug discovery and what the main challenges and solutions are for their successful generation and application of these models.

Traditionally, target-based drug discovery has focused on biochemical assays or non-physiologically relevant cell-based assays. Biochemical assays are highly suitable for high-throughput screening (HTS), but it is difficult to predict the in vivo therapeutic potential of the hits found. Cell-based assays offer a more complex cellular environment and the possibility to evaluate the phenotypic effect of compounds. However, traditional cellular models, such as immortalised cells, present several limitations regarding disease modelling and translatability to the clinic. As an alternative, primary human cells provide more representative responses, although they have a significant donor-to-donor variability and are rarely available in large-enough quantities for HTS, especially for less accessible organs such as the heart or brain.

Animal models do offer an in vivo complex environment, but are more expensive, have serious scalability constraints and the substantial inter-species differences hamper modelling of certain human diseases, such as cardiac arrhythmias or neurodegenerative diseases.

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