- iPSC technology is moving from a boutique phenomenon to industrialized cellular models.
- Increasing recognition by industry and regulatory bodies for detecting a variety of toxicities.
- Emerging utility for predicting cardio and neuro-related oncology adverse effects.
What is the current ‘state of the field’ for human induced pluripotent stem cell (hiPSC) derived tissue?
Over the past decade, there have been tremendous advancements in induced pluripotent stem cell (iPSC) technology and utility. Since its inception in 2007, with the revolutionary work of Dr. James Thompson at the University of Wisconsin-Madison (Madison WI USA), and Dr. Shinya Yamanaka at the Center for iPS Cell Research and Application at Kyoto University (Tokyo Japan) and subsequent recognition with a Nobel Prize in Medicine or Physiology in 2012, iPSCs have gained attention and notoriety as the technology has moved from scientific phenomenon to an implemented mainstay across industry and academia.
There is a significant need for human models in basic and applied research to fill the intertwined needs of developing more relevant experimental models while moving away from animal-based resources. Human iPSC technology meets these needs with the human origin fulfilling the promise of translatable models while allowing a migration away from, and reduction in the use of, animals in research. The technology also provides an opportunity to create donor-specific iPSCs to enable previously unattainable studies of human tissues across multiple genetic backgrounds from samples with corresponding clinical or demographic data. Several groups have been involved in establishing iPSCs as a cutting-edge scientific tool.
One of the earliest and arguably the most influential has been Cellular Dynamics International (CDI), a Fujifilm company. Based in Madison Wisconsin, CDI has led the way in launching the technology as an industrial enterprise and making it commonplace across Big Pharma and Biotech companies. The first, and perhaps most vital component of this effort, was defining rigorous manufacturing processes for proper care and control of the highly plastic iPSC population. Second was the development of relevant and robust models (i.e., iCell Cardiomyocytes, iCell GlutaNeurons, and others) which CDI achieved in large part through pharmaceutical and academic-based partnerships. Together, these have enabled large scale studies with pure consistent differentiated cells and has solidified CDI as a leader in the field.
The key to the successful transition from laboratory observation to industry workhorse was predicated upon a faithful recapitulation and interrogation of the desired human biology. Both pillars are demonstrated by the relatively large (>100) number of peer reviewed publications and industry-wide use of CDI iCell and MyCell iPSC-derived tissue. For example, early investigations at F. Hoffman-La Roche demonstrated that iCell Cardiomyocytes were a superior model for detecting QT prolongation and cardiac arrhythmia (Guo et al., 2011, 2013). This was followed by Merck and others using Ca2+ signaling as a surrogate marker for electrical activity (Zeng et al. 2016, Pfieffer et al, 2016), extended to predicting adverse drug-induced effects on contractility by AstraZeneca (Scott et al., 2014, Pointon et al., 2016) and even unraveling complex drug-drug interactions (Lagrutta et al., 2016).
Another example of the iPSC revolution is in oncology therapy, which has been plagued by cardiotoxic and other adverse effects arising from both extended patient survival uncovering latent toxicities as well as unanticipated adverse events from new treatments. Here again CDI iPSC-derived tissue cells are proving to be essential; from the use of iCell Cardiomyocytes for unraveling and predicting small molecule kinase inhibitor-mediated toxicity (Lamore et al., 2017), to accurately detecting off-target toxicity of T-cell receptor therapy (Cameron et al., 2013) and monoclonal antibody induced toxicity (Necela et al, 2017), or using iCell Neurons as a human-based model for chemotherapy-induced peripheral neuropathy (Wheeler et al 2015 Komatsu et al 2015 Morrison et al. 2016).
Government agencies and initiatives (e.g., FDA, HESI, JiCSA, CSaHI) are also recognizing the advantages of a consistent source of reproducible human material provided by iPSC technology. This is shown in the success of the Comprehensive in vitro Proarrhythmia Assay (CiPA) and Consortium for Safety Assessment using Human iPS Cells (CSAHi) initiatives and the large number of associated publications. These initiatives are helping to shift the paradigm of proarrhythmia testing and will likely be incorporated, in some form, into future International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use regulatory guidelines.
A separate example of iPSC acceptance by regulatory agencies is the approval of iCell Neurons by the FDA and EMA as a replacement for rodent-based testing in botulinum toxin release assay. These examples and others are significant milestones demonstrating the quality and acceptance of iPSCs to meet regulatory guidelines.