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European Biopharmaceutical Review

Patient in a Dish

Use of induced pluripotent stem cells to create innovative, first-in-class medicines shows much promise. However, before the benefits can be reaped from the ‘patient in a dish’ approach, a number of challenges still need to be overcome

It is axiomatic that drug discovery and drug development efforts have significantly improved the quality of life in the modern era. However, it is also a near universal truth that better models which are more reflective of the target biology or pathology would have the dual effect of significantly increasing the efficiency of the development process, as well as the safety and efficacy of new chemical entities. The advent of human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) may provide such models (1,2). The pluripotency and self-renewing capacity of stem cells offers a nearly limitless supply of biological source material for generating terminal tissue cells, while the human origin of these cells in turn may provide a relevant substrate upon which future drug discovery processes can be built. In addition, iPSC-derived tissues have the benefit of avoiding many of the ethical concerns of ESCs, while enabling the incorporation of genetic diversity.

The potential of stem cell derived tissue cells as models for drug development has been suggested in recent publications highlighting their recapitulation of in vivo physiology. For example, human stem cell derived cardiomyocytes show the expected genomic profiling, complement of ion channels, bioenergetic processes, and contractile activity (3-6). Similarly, iPSC-derived neurons also present a novel cellular model with in vivo-like electrophysiology, tau secretion and sensitivity to botulinum neurotoxin (7,8). This potential for stem cell derived tissue cells as drug discovery models is further established in their use as a springboard to Phase 1 clinical trials and as a predictive toxicology tool (9,10). Although these are a few illustrations of the advances made in the use of stem cell derived tissue cells, care should be taken not to ‘oversell’ the technology as it is still in relative infancy and advances in cellular functionality will offer even greater use.

Using Stem Cell Derived Models in Drug Discovery
Improvement in the quality of healthcare has resulted in a worldwide increase in life expectancy, but this has also brought about a paradoxical significant increase in the prevalence of chronic progressive disorders, particularly of the cardiovascular, metabolic and neural systems. This statement is backed up by the number of people with diabetes mellitus worldwide; the number has more than doubled over the past three decades and is projected to rise to 439 million by 2030.

Despite huge investments by the pharmaceutical industry to develop new therapeutic modalities for such disorders, very few new medicines are entering the market. Drug discovery has proven to be challenging due to the use of experimental tools which recapitulate subsets of the specific features of human disease. The advent of patient-specific iPSC technology represents a revolution in medical science, allowing the study of both normal and disease pathophysiology in different genetic backgrounds and their response to drugs very early in the drug discovery process. An interesting analysis among the first-in-class drugs with new molecular mechanism of actions (MMOAs) shows that the contribution of phenotypic screening to the discovery of such molecules exceeded that of target-based approaches (11). We postulate that the advent of the iPSCs ‘patient in a dish’ – concept, where the aim is to identify multiple disease-relevant cellular phenotypes – will offer an unprecedented resource to better investigate disease

biology and ultimately determine the identification of innovative first-in-class medicines (12). Here, we will refer the current state of the use of the iPSCs in drug discovery with respect to cardiac and neural disorders. We will attempt to report the hurdles, risks and possible rewards that the pharmaceutical sector will face when implementing such technology.

Implementing iPSC Technology in Pharma

Human iPSCs have been generated from several tissues using a variety of approaches. Initial reprogramming efforts used vectors that were inserted into the genome and then silenced post-iPSC generation. The alteration of the host genome has given rise to ‘what if’ speculations of altered function, however such concerns have been unfounded to date. Nevertheless, given the reported variability among human pluripotent cell lines with regard to epigenetic information, expression profile and differentiation properties, their effective implementation in the drug discovery process relies much more on making the right things more, rather than doing things right. To that end, newer reprogramming technologies which avoid insertional mutagenesis or transgene reactivation should be the preferred tool as the field moves forward.

Such non-integrating methods will also further enable the transition to iPSC-based transplantation therapies in the future. Many laboratories are implementing F-deficient Sendai Viruses and transient transfection with episomal vectors as preferred reprogramming methods (13). For similar reasons, the use of reprogramming factors with oncogenic potential should be avoided. The use of c-Myc could be substituted with L-Myc and c-Myc mutants, which have shown more efficiency and specificity to generate human iPSCs.

The generation and maintenance of iPSC lines is envisioned to be performed in dedicated core facilities using common reagents and following stringent standardised operating procedures to better facilitate inter-laboratory comparisons and compatibility. The concept of using iPSCs from clinical populations as a ‘patient in a dish’ has to fulfil important prerequisites, mainly related to the choice of the right controls. This aspect is even more relevant if we consider that every person has disease-associated single-nucleotide polymorphisms. Therefore, the perfect ‘non-diseased/healthy’ control may not exist within the population, but as explained below, may be able to be fabricated in the laboratory.

iPSC technology is particularly amenable to investigating penetrant monogenetic diseases in which the relationship between genotype and phenotype is more direct, and because an ad hoc isogenic control is represented by genetically rescued cell lines. The transcription activator-like effector nucleases (TALENs) now allows one to genetically rescue the patient specific monogenetic alterations to generate genotyped matched lines without the mutation, which may indeed provide the ‘perfect’ control. Moreover, the TALENs technology – in synergy with the recent reports for the generation of murine haploid ESCs – provides a potentially important advance for forward and reverse genetics in order to target identification and modelling disease pathways in mammalian cells. For multifactorial disorders, a good control cell line is represented by cell lines derived from healthy siblings, which may contribute to decreases in background confounding factors. In the event that such samples cannot be obtained, an alternative is to compare specific patient population with extreme ‘fast versus slow progression’, ideally matching different genders, ethnic and genetic backgrounds. Particularly for such diseases of unknown genetic origins, it must be clear which cells in a tissue are the major contributor of the disease pathophysiology, although even this may be unknown still for some diseases. In addition to selecting the correct patient population and appropriate controls, a suitable differentiation protocol(s) must be chosen for the cell type(s) of interest to enable suitable maturation and detection of the cellular disease pattern. For diseases with low penetrance and late-onset phenotypes, the iPSC-derived cellular models may be treated with stressors mimicking the disease specific micro-environmental factors (see Figure 1).

Several studies have reported a proof of concept (PoC) that human iPSCs can be used to model diseases ‘in a dish’ recapitulating specific disease traits. Cardiovascular diseases were among the first where successful PoCs have been generated. Prominent examples are long QT syndromes (LQTSs) that are caused by mutations in ion channel genes. Moretti and colleagues not only reported that the duration of the action potential was markedly prolonged in the myocyte cells derived from patients, but for the first time introduced the concept of rescuing the phenotype from pharmacological intervention (14). Indeed pretreatment with a nonselective beta-blocker substantially blunted the effect of a chronotropic agent (isoproterenol) in myocytes from patients with long-QT syndrome type 1.

More recently, PoCs have been reported for inherited cardiomyopathies associated with a mutation in a sarcomeric protein (15). Indeed, the R173W point mutation in the cardiac muscle troponin T could recapitulate some morphological and functional characteristics of dilated cardiomyopathy (DCM) in vitro, such as altered sarcomere disarray, impaired Ca2+ kinetics, and decreased contractility. They have also shown in this study that overexpression of Serca2a markedly improves the contractility of DCM iPSC-derived cardiomyocytes. These results are intriguing, especially considering that a Sereca2a gene therapy treatment is under evaluation in clinical trials for heart failure. Identifying small molecules that can resolve the deficiency in contractile force production in DCM-cardiomyocytes may present a possible new avenue to treat end stage heart failure disease.

In the neuroscience context, many different examples have been achieved as well. For example, patient-specific iPSCs lines for modelling Parkinson’s disease (PD) have been described. In particular, iPSC-derived dopaminergic neurons bearing mutations in Leu-rich repeat kinase 2 (LRRK2), a gene causing a significant age-associated cumulative risk for a form of PD, showed an increased response to oxidative stressors (16,17). More recently, Israel and colleagues probed sporadic and familial Alzheimer’s disease (AD) using iPSCs and reported phenotypes relevant to AD, even though it can take decades for overt disease to manifest in patients (18).

One of the two patients with sporadic AD exhibited significantly higher levels of the pathological markers amyloid-b (1-40), phospho-tau (Thr 231) and active glycogen synthase kinase-3b (aGSK-3b); as did two patients with familial AD, both caused by a duplication of the amyloid-b precursor protein gene (APP).

The use of large-scale screening using familial dysautonomia iPSCs enabled the identification of compounds that rescue inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein (IKBKAP) expression (19). Target identification for the identified phenotypic hit SKF-86466 implicated the discovery of the adrenergic receptor pathway in regulating IKBKAP expression. By providing cellular systems that closely resemble human cell biology and pathophysiology in vitro, the iPSC technology will realise the possibility of conducting ‘in vitro Phase 3 studies’. In particular in this visionary proposal, a shared consensus from the EMA, the FDA and the pharmaceutical industry will be essential to create clear guidelines, standard SOPs, and well-validated iPSC line collections with different ethnic and genetic backgrounds. In conclusion, the ‘patient in a dish’ approach definitely retains all the potentials to trigger a new era in drug discovery, but numerous challenges still need to be overcome before its clinical translation is complete.


Drug discovery and development is a dynamic process that has yielded great successes and yet faces continual challenges. ESC and iPSC technologies and related methods provide one avenue through which some of these challenges can be overcome. These technologies have brought relevant human targets and systems into the drug development pipeline earlier than ever before, enabling mechanistic investigations into human biology and pathophysiology and predictive toxicology from healthy and clinical populations. Continued effort at improving the ESC and iPSC tissue cell models will only strengthen the foundation upon which these early successes are built.


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  2. Yu J, Vodyanik MA, Smuga-Otto K et al, Induced pluripotent stem cell lines derived from human somatic cells, Science 318: pp1,917-1,920, 2007
  3. Babiarz JE, Ravon M et al, Determination of the human cardiomyocyte mRNA and miRNA differentiation network by fine-scale profiling, Stem Cells Dev 21: pp1,956-1,965, 2012
  4. Ma J, Guo L et al , High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents, Am J Physiol Heart Circ Physiol 301: H2,006-H2,017, 2011
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  6. Puppala D, Collis LP et al, Comparative gene expression profiling in human induced pluripotent stem cell derived cardiocytes and human and cynomolgus heart tissue, Toxicol Sci, Published online ahead of print, 2012
  7. Chai X, Dage JL et al, Constitutive secretion of Tau protein by an unconventional mechanism, Neurobiol Dis 48(3): pp356-366, 2012
  8. Whitemarsh RC, Strathman MJ et al, Novel application of human neurons derived from induced pluripotent stem cells for highly sensitive botulinum neurotoxin detection, Toxicol Sci 126(2): pp426-435, 2012
  9. Reynolds JG, Geretti E et al, HER2- targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity, Toxicol Appl Pharmacol 262: pp1-10, 2012
  10. Guo L, Abrams RM et al, Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell derived cardiomyocytes, Toxicol Sci 123(1):pp 281-289, 2011b
  11. Swinney DC and Anthony J, How were new medicines discovered? Nat Rev Drug Discov 10: pp507-519, 2011
  12. Grskovic M, Javaherian A, Strulovici B and Daley GQ, Induced pluripotent stem cells-opportunities for disease modelling and drug discovery, Nat Rev Drug Discov 10: pp915-929, 2011
  13. Fusaki N, Ban H, Nishiyama A et al, Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome, Proceedings of the Japan Academy 85: pp348-362, 2009
  14. Moretti A, Bellin M, Welling A et al, Patient-specific induced pluripotent stem-cell models for long-QT syndrome, N Engl J Med 363: pp1,397-1,409, 2010
  15. Sun N, Yazawa M, Liu J et al, Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy, Sci Transl Med 4: p130ra147, 2012
  16. Batista LF, Pech MF, Zhong FL et al, Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells, Nature 474: pp399- 402, 2011
  17. Nguyen HN, Byers B, Cord B et al, LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress, Cell Stem Cell 8: pp267- 280, 2011
  18. Israel MA, Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells, Nature 482: pp216-220, 2012
  19. Lee G, Ramirez CN, Kim H et al, Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression, Nat Biotechnol, Letter 25 November 2012

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Roberto Iacone is leading the Stem Cell Group at Roche, in Cardiovascular and Metabolic Discovery. He focuses his research on the use of the patient specific induced pluripotent stem cells technology as a translational in vitro model to investigate pathophysiological mechanisms associated with diabetes type 2 cardiovascular complications. Roberto gained his PhD at the Max Planck International School in Dresden, Germany, for his work on stem cells and lineage commitment.

Blake Anson
received his doctorate in Neuroscience from the University of Oregon, US; undertook postdoctoral training at the University of Wisconsin-Madison US, in Molecular Genetics; and then moved to an assistant scientist position in Cardiovascular Research under Craig T. January at the University of Wisconsin Medical School, examining hERG channel physiology and pharmacology from healthy and clinical sources. He is currently the iCell Cardiomyocyte Product Manager at Cellular Dynamics International.
Roberto Iacone
Blake Anson
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