How iPS cells are changing drug development and disease modelling

Masin Abo-Rady

by Masin Abo-Rady

Drug development is a long and extremely expensive process. Failures in late-stage clinical trials due to lack of effectiveness and unanticipated side effects are main reasons for the high costs [1]. Severe adverse events, hepatotoxicity and cardiovascular toxicity, which in part can even lead to patient death, present the critical need for more precise medicine. The main problem with present preclinical assays is their inability to reliably detect and predict potential damage to liver, heart, brain and other organs. Additionally, there is a lack of animal models, which show the same pathophysiology as humans. Mice and other models differ from humans in genetics, physiology and immune system, and thus do not reliably recapitulate the disease as it occurs in patients [2]. Human primary cells, such as neurons and cardiomyocytes could overcome the difficulties of disease recapitulation but limited access, ethical concerns and their inability to be expanded excludes them as suitable disease models [3].

In 2006, Shinya Yamanaka and colleagues made a ground-breaking discovery that turned out to be well-suited to overcome these problems. By overexpressing specific transcription factors the researchers were able to reprogram mature somatic cells into induced pluripotent stem cells (iPSCs). Those cells have the unique abilities to proliferate unlimitedly and differentiate into almost every cell type of the human body. As they can be produced from easily accessible sources like skin biopsies or blood, iPSCs do not raise the ethical concerns that accompany primary cells or embryonic stem cells. Thus, iPSCs are helpful to study human disease aetiology, identify pathological mechanisms and develop therapeutic strategies for tackling diseases [1]. In recent years it was confirmed that cells differentiated from patient-specific iPSCs were able to appropriately recapitulate disease mechanisms that are found in humans. By generating specific cell types affected by a certain disease, iPSCs are used to create disease models in a dish and to study disease relevant cell types that are otherwise inaccessible. Together with the opportunity to generate disease specific cells in an unlimited amount, iPSCs therefore represent a suitable model for drug screenings and help predict effectiveness of drug candidates, as well as their pharmacology and toxicity in humans (see Figure 1).

Figure 1: Drug screening and disease modelling using patient-specific induced pluripotent stem cells.

Establishing iPSC-based models led to a shift in drug discovery from target to phenotypic screening, as patient-derived iPSCs can mirror molecular and cellular phenotypes found in patients. Utilizing this advantages, pharmaceutical companies can now test hypotheses of drug mechanisms in vitro in a cost-effective manner before initiating timely and expensive clinical trials. For example, one critical difficulty in clinical trials is the selection of the right target population. Due to differences in genetic background and predisposition, patients with the same disease and pathology can differ significantly in their drug response and the variety of adverse events. Generating patient-specific cell types offers the possibility to conduct in vitro “clinical trials”, in which drugs can be tested for toxicity and efficacy. This leads to more precise identification of effective drugs, which can then be tested and correlated in vivo in the same patients. As a result, these in vitro studies can lead to improved patient stratification, lower compound attrition rates and identification of safer drugs. Beside the development and screening of new drugs, iPSC-based models can be used to identify already available drugs, to be repurposed for the treatment of diseases with high medical need but little to non-exiting therapeutic options. As an example, ezogabine, an anti-epileptic drug, showed efficacy in iPSC-derived motor neurons to model amyotrophic lateral sclerosis (ALS), leading to the subsequent initiation of clinical trials [4].

In classical drug development assays, the results from disease models are compared to healthy controls. But just like patients, healthy control cells differ in their genetic background and drug-response. Even iPSCs can show significant line-to-line variation. Genetical modification techniques, such as CRISPR/Cas9, present an elegant way to overcome this problem. By generating site-specific DNA double strand breaks, disease-causing mutations can be inserted into control iPSCs or alternatively be corrected in iPSCs from patients with a genetic disease cause. In this way the mutant and gene-corrected cell lines share the same genetic background and all phenotypic differences are solely due to the mutation itself, making gene-corrected cells the perfect control.

With all the great advantages of iPSCs as disease models, one critical problem is the molecular maturity of iPSC-derived cells, which exhibit immature characteristics comparable to embryonal or fetal cell phenotypes. Particularly for modelling late-onset diseases, however, maturity is a critical aspect, for example Alzheimer’s Disease, Parkinson’s Disease and ALS. Approaches to tackle this problem and simulate defined aging include chemical induction of mitochondrial stress, inhibition of protein degradation, specific culture medium formulations and overexpression of progerin, a truncated version of the premature aging protein lamin A [3].

Taken together, human iPSCs present a powerful tool to model diseases in a dish and to identify safer and more effective drug candidates. Constant improvement of fast and efficient differentiation protocols and culture techniques, as well as developing 3D organoid cultures to study disease mechanisms in a more complex system, will improve drug development and minimize the use of poor-suited animal models. In this way companies can save investments ranging up to millions by preventing late-stage clinical trial failures.

Biopharma Excellence is experienced in the development of new drugs and Advanced Therapy Medicinal Products (ATMPs) that utilize iPSCs. We understand the unique challenges and have comprehensive expertise and a proven track record in the development of this product class. If you want to learn more about our services in this area, please get in contact with us.


  1. Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a decade of progress. Nature reviews Drug discovery. 2017;16(2):115.

  2. BioInformant. Stem Cells in Drug Discovery: A changing Paradigm  [Available from:

  3. Doss MX, Sachinidis A. Current challenges of iPSC-based disease modeling and therapeutic implications. Cells. 2019;8(5):403.

  4. McNeish J, Gardner JP, Wainger BJ, Woolf CJ, Eggan K. From dish to bedside: lessons learned while translating findings from a stem cell model of disease to a clinical trial. Cell stem cell. 2015;17(1):8-10.

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