In this article, the present and future outlook for human iPSC derived tissues is explored. Induced pluripotent stem cells (iPSCs) are differentiated cells that are reprogrammed into a pluripotent state, allowing a wide range of cell and tissue types to be derived from them.
Key findings include:
- 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.
Human iPSC derived tissue
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 was Cellular Dynamics International, now FUJIFILM CDI (FCDI) as FUJIFILM acquired CDI for $307 million in 2015. Based in Madison Wisconsin, FCDI 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 FCDI 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 FCDI as a leader in the field.
Human iPSCs as an Industry Workhouse
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).
Human iPSCs in Oncology
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 Initiatives for Human iPSC Technology
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.
iPS Cell Research
With both iPS cell research and clinical activity expanding, the market for iPSC-derived tissues is poised to experience rapid growth. With more than 200 different cell types in the human body, a key goal of FCDI is to continue to expand the portfolio of available human iPSC-derived tissues where possible and where there is a scientific need. For example, FCDI’s first-generation GABAergic iCell Neurons are inhibitory cortical neurons that recapitulate many features of human neurons.
The utility of this cell type was immediately demonstrated as an alternative model to primary animal-based neuronal preparations for assessing neurite outgrowth as well as developmental and general neuronal cytotoxicity. However, as they are a primarily inhibitory neuronal population, they provided limited utility for assessing networked neuronal electrical activity.
For this reason, the second generation of primarily excitatory glutamatergic iCell Glutaneurons were developed. These neurons, when coupled with MEA technology, allow iPS cell researchers to evaluate networked neuronal electrical activity and spontaneous bursting in vitro, thereby providing a previously unattainable human neuronal model to test excitotoxicity and electrical (seizurogenic) activity.
Like iCell Cardiomyocytes and iCell Cardiomyocytes2, iCell Glutaneurons have entered large-scale consortia work. Specifically, the NeuTox HESI initiative aimed at developing a predictive seizurogenic assay. The same success is expected for NeuTox with iPSC-derived neurons as has been observed in the cardiovascular field with iPSC-derived cardiomyocytes and the CiPA and CSAHi initiatives.
iPSC technology has made significant contributions to the biologists’ toolbox and will continue to advance the frontiers of iPS cell research. In 2016, Cynata Therapeutics (ASX:CYP) commenced the world’s first clinical trial involving an allogeneic iPSC-derived therapeutic product, which it derived from CDI’s iPSCs.
Today, Cynata is investigating its iPSC-derived cell therapeutics for the treatment of graft-versus-host disease (GvHD) critical limb ischemia (CLI), osteoarthritis (OA), and respiratory failure/distress, including ARDS. Notably, Cynata’s Phase 3 trial of its investigational product CYP-004 has enrolled 440 patients, making it the world’s first clinical trial involving an iPSC-derived cell therapeutic product to enter Phase 3 and the largest trial ever completed with an iPSC-derived cell therapeutic.
Furthermore, dozens of companies and organizations are now commercializing iPSC-derived cell therapeutics. Similarly, growing numbers of researchers are investigating methods to enhance the functionality of terminally differentiated cells types. Most of the research to date has focused on iPSC-derived cardiomyocytes, hepatocytes, and neurons. Enhanced functionally will likely result from multiple tactics including both pre-and post-differentiation strategies.
Toward this goal, one school of thought supports the use of complex culture systems such as 3D culture techniques and co-culture strategies, with multiple cell types, to better recapitulate the in vivo microenvironment (e.g., organ-on-a-chip).
In the case of iPSC-derived cardiomyocytes, 3D culture and continuous pacing has been shown to enhance or provide missing functionality such as positive force-frequency relationship and enhance positive inotropic response (Zhang et al 2017, Feric et al., 2017, Ravenscroft, et al., 2016). In addition, iPSC-derived hepatocytes have shown superiority over many immortalized hepatocyte lines (Gao et al., 2017) and 3D culture strategies improve their functionality including increasing CYP activity (Hancock et al., 2017).
While one of the main characteristic of iPSC technology is the ability to study samples from different genetic backgrounds, the reality is that most commercially available iPSCs are from apparently healthy sources, many groups do not have access to patient samples or the infrastructure to manufacture at scale, or the resources to genetically engineer specific models.
Thus, there is a significant need to make more iPSCs and iPSC-derived tissues to better represent healthy and diseased populations and to make these resources available to the larger research community.
Toward this goal, FCDI is extending its portfolio of iPS cell research tools to include an array of disease and diverse populations. One effort at FCDI is to provide access to diverse populations for personalized toxicity testing or clinical trial “in a dish.” FCDI is also committed to developing cell banks for the research community. Together, these efforts will continue to position the company as a leading partner for iPSC-based research across academia and industry.