The tantalizing prospect of using induced pluripotent stem cells to develop new drugs is looking better and better

In 2006, when Shinya Yamanaka published his seminal work on reprogramming mouse fibroblasts into pluripotent stem cells, I was a PhD student at Cambridge University working on embryonic stem cells. I still remember how impressed and excited I was when I first read his manuscript. The idea that you could take fully differentiated cells, re-program them into immature stem cells—what we refer to as induced pluripotent stem cells or iPSCs—and  then use them to grow any cell or tissue type completely revolutionized our understanding of cell biology. Moreover, transferring the technology from mice to humans, including to patients diagnosed with a disease, has opened the door to the development of novel tools for modelling disease and drug discovery. Indeed the number of iPSC lines that have been successfully derived from patients has been increasing rapidly over the past 10 years. Introducing human stem cell technology into the various aspects of drug discovery, such as compound screening, toxicity testing and target validation, has the potential to reduce failure rates and increase the chances of success in clinical trials.

Although reprogramming methods and differentiation protocols have been improved in recent years, the number of high throughput screenings that have implemented the use of patient-derived stem cells is still relatively low. Multiple factors account for why iPSCs are not used a lot in drug discovery.

Neurons differentiated from stem cells derived from Huntington’s disease patient.

Scientists face difficulties associated with variability of patient- derived iPSCs, which are thought to be related to variation in reprogramming efficiency. In other words, the iPSC retain features of their cell type of origin. Secondly, existing protocols developed to differentiate iPSCs into a specific cell/tissue type can be technically demanding, time consuming and difficult to replicate. Lastly, major work is still required to validate iPSC-derived cell differentiation models ensuring that the cells recapitulate cellular phenotype as well as potential disease-specific features. 

Four and half years ago I joined Charles River as a senior scientist with the challenging task of establishing a stem cell platform suitable for high throughput screenings and target validation. Although we encountered many challenges, including the ones mentioned above, I am pleased to say that we also made significant progress. We successfully established a high throughput screening stem cell model as part of a project that aimed to identify small molecule drugs in the treatment of Huntington’s disease, an inherited disease of the central nervous system. Additionally, development of robust quality control assays that led to improvement and reproducibility of differentiation protocols has now brought us several steps closer to applying iPSCs to many more future projects.

In the next 5 to 10 years I would love to see high profile examples of novel drugs being developed with iPSC-derived models playing a key role in the various phases of the drug discovery process, such as incurable CNS diseases like Huntington’s or Parkinson’s. This would help to boost confidence and increase investments within pharmaceutical companies for the use of stem cells in their drug discovery pipelines.

If this occurs, I think we can expect major discoveries from this rapidly evolving field in the not too distant future.

If you are interested in learning more about the use of stem cells in HTS, check out this recent webinar.