Exploring iPSCs for individual and population health applications

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Brad Hamilton, Founder and Chief Science Officer at GoodCell examines the potential of induced Pluripotent Stem Cells.

Across the world, patients suffering from heart failure, donor organ rejection and many other life-altering illnesses are struggling to combat the symptoms of their conditions. What if there was a way to directly repair or replace tissues that have been damaged by certain disorders? The Nobel-prize winning discovery of a way to turn adult cells into cells akin to embryonic stem cells—capable of making any cell type in the body—is making that possible.

Due to their versatility, induced Pluripotent Stem Cells (iPSCs) are becoming a powerful force in science and medicine. They hold the potential to pave the way for personalised therapies for heart failure, Parkinson’s Disease and adult-onset blindness, among other conditions. In the long-term, tissues and potentially whole organs made from iPSCs from the patient’s own cells could greatly reduce or eliminate the risk of organ rejection. Today, they are already a valuable new tool for drug development. We’ve only just scratched the surface of their potential.

For example, researchers at the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden, Harvard University and the University of Bonn have found a ‘recipe’ to more easily convert iPSCs1 into a wide variety of cell types and tissues that can be used for drug testing and cell replacement therapies. Demonstrating that just a single transcription factor is sufficient in each case, the researchers found a total of 290 DNA-binding proteins that quickly and efficiently reprogrammed stem cells into target cells, greatly reducing one of the cumbersome aspects of using iPSCs.

Numerous companies are developing next generation manufacturing methods for research and clinical grade iPSCs to foster the development of advanced iPSC-based therapeutics and drug development tools. Recent studies reveal2 how an optimised protocol employing vertical-wheel bioreactors is capable of achieving the rapid generation of clinically-relevant numbers of iPSCs that can be safely employed for various therapeutic purposes.

These versatile cells also provide cost savings in drug development. One example can be found in cardiac toxicity, a significant issue for cancer drug makers because it renders the drugs unusable and is typically only identified after conducting extremely expensive early clinical testing. Using heart cells made from iPSCs in the development of cancer drugs can uncover the toxicity early, saving time and money through pre-clinical testing. In the Stanford Lab of Joseph Wu, a GoodCell Scientific Advisory Board (SAB) member, they have used heart cells grown from iPSCs to develop a ‘cardiac safety index’3 that can grade the potential for trial-ending side effects in advance.

Given their inherent benefits, the industry has a tremendous opportunity to continue harnessing the power of iPSCs and finding ways to bring these therapies to market faster and more effectively -­ both for the benefits of individuals and drug developers.

Breakthroughs revolutionising drug discovery

Impact of Covid-19

Covid-19 lit a fire under the industry to collaborate in ways never before seen. One particular result of these collaborations is the development of iPSC-derived in-vitro models to study the virus. More specifically, they are being used to assess the cardiovascular effects of the viral infection, as well as the impact of antiviral drugs. Presently, there are no alternative in-vitro human cardiac models, other than primary tissue.

Most studies previously used in clinical trials derived from sources such as human cancer cell lines. While these cell lines are capable of reflecting virus entry or sustaining viral replication, they are unable to reveal tissue-specific physiology necessary to understand why some organs are affected differently than others.

With human iPSCs in Covid-19 research, the cellular and molecular host-virus interactions can be examined, including the mechanisms through which cardiovascular cells are infected by SARS-CoV-2 and potentially the identification of long-term effects of the infection on recovered patients. Additionally, repurposed drugs can be screened for their potential effectiveness in combating the virus, as well as for examining cardiac cytotoxicity, a possible secondary risk for patients faced with Covid-19. These provide a preclinical platform essential for Covid-19 drug testing.

Furthermore, a recent report4 explained how exposure of iPSC-derived heart cells to SARS-CoV-2 revealed productive infection and rapid transcriptomic and morphological signatures of damage in cardiomyocytes. These cytopathic-specific features provide insights into how the virus leads to cardiac damage. They also offer the opportunity for potential therapeutics and could provide insight into the long-term effects of COVID-19.

Organoid technology

The explosive growth of organoid technology is undeniable, and much of it depends on the versatility of iPSCs. Future Market Insights (FMI) predicts5 the global organoids market will reach an estimated $44.2M just this year. With organoids and 3D cell cultures becoming more popular, experts believe they will replace 2D cell culture previously used in traditional research methods. To more efficiently address the alarming rise in the prevalence of cancer, the scope of applications for organoids in oncology research is essential.

The use of iPSCs to develop organoids to test drugs in models of the liver, heart, retina, brain and intestines is revolutionising the drug testing space6. 3D bioprinting enables further precision in the manipulation of organoid size, cell number and confirmation. For example, bioprinting also functions as a means of creating the tissue layers needed for kidney organoids to be used in drug testing. Through automating extrusion-based bioprinting for kidney organoid production, better quality control, scale, structure, in-vitro and in-vivo applications of stem cell-derived human kidney tissue can be facilitated.

Repurposing an approved drug for ALS

According to a recent study,7 epilepsy drug Ezogabine decreased cortical and spinal motor neuron excitability among ALS participants, revealing that neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials. This marks the first ALS clinical trial to test a finding made possible through stem cells.

Prior to these findings, GoodCell SAB member Kevin Eggan of Harvard, used iPSC models of ALS to discover that motor neurons tend to show increased electrical activity that leads to dying of exhaustion in the disease. As such, the ezogabine drug could be utilised to effectively slow down over activated motor neurons in clinical trials. Given the drug was already FDA approved, ezogabine was able to effectively bypass further lab work and proceed to early phase patient trials.

Another recent development in research using lab-based models to develop and test new therapies for ALS comes from researchers from the VIB, Center for Brain & Disease Research, Laboratory of Neurobiology in Leuven, Belgium. According to reports,8 they have developed a new miniaturised model to provide further insights into ALS by generating a co-culture of iPSC-derived motor neurons and human primary mesoangioblast-derived myotubes in microfluidic devices. The versatile and reproducible in-vitro model of a human motor unit provided further insights into ALS by investigating more closely the effect of ALS-causing mutations. This is just another means of how ALS patient-specific iPSC models helped to accelerate the advancement of drug discovery in order to provide more effective, calculated treatment.

Cell therapies in late-stage development

The field of cell therapy is rapidly accelerating. The FDA has estimated9 it will receive more than 200 applications to begin new cell and gene therapy clinical trials per year. These will add to the more than 670 cell- and gene-modified cell therapies currently underway. By just 2025, the agency expects to approve 10-20 cell and gene products a year. There are a multitude of therapies in development that may pave the way for treatment of a variety of conditions.

Age-related macular degeneration

Age-related macular degeneration (AMD), the leading cause of adult-onset blindness, is proving to be the furthest along in its clinical treatment trials. Researchers at the National Eye Institute (NEI) have launched a clinical trial10 that tests the safety of a novel patient-specific, stem cell-based therapy to treat geographic atrophy (the advancement of AMD). Presently, the geographic atrophy form of AMD doesn’t have any treatment options. The first US clinical trial uses replacement tissues from patient-derived iPSCs made from the patient’s blood cells. Then they can be programmed to become retinal pigment epithelial (RPE) cells, hoping to replace the dying cells with healthy iPSC-derived RPE cells.

Additionally, on March 22, the New York Stem Cell Foundation announced11 they are developing a stem cell therapy to treat patients suffering from the disease. Scientists will create healthy RPE cells from iPSCs that are generated from each patient’s blood cells to replace the damaged eye cells and restore vision. This will function as the critical groundwork for future cell therapies targeted toward other major diseases.

A team in Japan was the first to begin a clinical trial using iPSCs to generate RPE and treat AMD. That trial is ongoing.

Parkinson’s Disease

There are more than 10 million people worldwide12 living with Parkinson’s Disease, which has become another area in which researchers are developing innovative therapies. Aspen Neuroscience is one of the biotechnology players at the forefront of this research, focused on using a person’s own cells for replacement therapy to provide breakthrough treatment for Parkinson’s patients13 in rapid timing. One of its products, ANPD002, combines gene correction and autologous neuron therapy for the treatment of genetic forms of the disease. Across the industry, we can expect to see more AI-based genomics tools being used for comprehensive targeting, as they are time-efficient and produce safe, replicatable and personalised cell therapies.

Beyond repairing genetic variants, iPSCs can also be used as a means of replacing cells that have died as a result of non-genetic forms of the disease. The cell type that depletes in Parkinson’s, for instance, are dopamine neurons. It is now possible to create dopamine neurons from iPSCs, the goal of which is to replace these directly within patients with Parkinson’s in the hopes of leading symptom-free lives. Aspen has a second trial planned to do this, as do several other teams.

Studies have shown14 a preference for tapping autologous cells, which use stem cells from a patient’s own body, rather than allogeneic cells (stem cells collected from a donor and transplanted into the patient). Through personalised medicine, a patient’s own skin or blood cells can be turned into stem cells and then, eventually, dopamine neurons that are implanted within the brain.

These advancements in cell transplant treatment are developing in parallel in the US, Japan and elsewhere around the world. Osaka-based drugmaker Sumitomo Dainippon Pharma, which already has a clinical trial underway in Japan, plans to begin American trials of its treatment15 using iPSCs to improve conditions of Parkinson’s disease. This marks yet another commercial commitment to utilising iPSCs to treat disease.

New path to treating cancer

Immuno-oncology companies are also implementing means of expanding access to the most innovative and effective cancer treatments through the generation of iPSCs. GoodCell’s co-founder and SAB member David Scadden, MD, has discussed how his company, Fate Therapeutics16, is establishing technologies to generate safe, efficient methods to create iPSCs that enable disease modelling, drug discovery and the development of personalised cell replacement therapy. The company has developed an innovative immuno-oncology platform that uses iPSCs to create banks of our immune systems natural killer (NK) cells that can target cancers. Those cells became the first iPSC-derived therapy in human trials in the US.

Exacis Biotherapeutics recently announced17 next steps in the preclinical development of its ExaNK engineered NK-cell therapy candidates. The company produces rejection-resistant ExaNK cells through performing function editing of stealthing targets in its proprietary mRNA-reprogrammed iPSCs. Using its high-yield differentiation process, Exacis differentiates engineered iPSCs to the final NK-cell product.


Over the past decade, researchers from the University of Tokyo have developed a device for the long-term transplantation of iPSC-derived human pancreatic beta-cells. The aim of this study was to aid in the treatment of type I diabetes mellitus (T1D).

The challenging approach to treating T1D, involves replacing lost beta-cells by means of cell therapy. The novel construct enables successful transplantation of beta-cells in the long-term. The present challenge researchers were faced with in this cell therapy was the fact that cells of the recipient could destroy the newly transplanted cells. As a preventative measure, they constructed a millimeter-thick LENCON graft, as these grafts have previously been shown to mitigate the body’s immune response to a foreign body. Through utilising its lotus root shape, cells were strategically implanted near the graft’s edge, enabling oxygen and nutrients to diffuse sufficiently and survive.

At least two US companies have similar strategies using beta-cells encased in a protective layer. Their clinical trials, one underway and one recently approved, use cells derived from embryonic stem cells. But the companies are also developing iPSC versions. 

The future of iPSCs

Recent animal studies have shown the breadth of what may be possible therapeutically with iPSC-derived tissue. From bioprinting of kidney tissue18 to mini livers19 and a whole functioning thymus20, researchers have consistently shown the ability to make complex tissues that function very much like the natural tissue.There is increasing evidence that iPSCs can reduce costs and improve monitoring and control across the drug development pipeline. With improvements in the use of these cells well underway, the potential of iPSCs is unmatched. Due to their versatility, they could become integral in repairing or replacing any damaged or defective tissue within the body. We expect companies will continue to focus on the mobilisation of cell manufacturing. The possibilities are endless in terms of the role iPSCs will play in pre-clinical research for a multitude of diseases, providing breakthrough science for researchers and therapies for patients around the world.

Volume 22, Issue 3 – Summer 2021

About the author

Brad Hamilton is the founder and Chief Science Officer at GoodCell. Prior to joining GoodCell, he was the Chief Technology Officer for ReproCELL, a multinational stem cell company focused on developing novel stem cell technologies and therapies.Hamilton’s work as a founding scientist and director of research for Stemgent helped develop groundbreaking RNA-mediated cellular reprogramming technologies, as well as applications for the generation of induced pluripotent stem cells from clinically accessible samples such as human skin, blood and urine.

Hamilton has both published and presented this work internationally. He holds an MS in biotechnology from the University of Tennessee—Knoxville, as well as a BS in Biology from James Madison University.


  1. https://www.sciencecodex.com/customized-programming-human-stem-cells-662113
  2. https://stemcellsportal.com/article-scans/deriving-clinically-relevant-numbers-human-ipscs-optimized-bioreactor-culture?utm_source=iContact&utm_medium=email&utm_campaign=rmw&utm_content=RMW+September+29
  3. https://stm.sciencemag.org/content/9/377/eaaf2584
  4. https://stm.sciencemag.org/content/13/590/eabf7872
  5. https://www.futuremarketinsights.com/reports/sample/rep-gb-8106
  6. https://www.nature.com/articles/s41563-020-00853-9
  7. https://jamanetwork.com/journals/jamaneurology/article-abstract/2773459?utm_source=undefined&utm_campaign=content-shareicons&utm_content=article_engagement&utm_medium=social&utm_term=120220
  8. https://www.genengnews.com/news/miniaturized-models-provide-a-bigger-picture-of-als/
  9. https://www.fda.gov/news-events/fda-newsroom/press-announcements?AhNyY=VsMKFsf&page=79
  10. https://www.nei.nih.gov/about/news-and-events/news/nih-launches-first-us-clinical-trial-patient-derived-stem-cell-therapy-replace-and-repair-dying
  11. https://www.news-medical.net/news/20210322/NYSCF-is-developing-new-stem-cell-therapy-to-treat-age-related-macular-degeneration.aspx
  12. https://www.parkinson.org/Understanding-Parkinsons/Statistics
  13. https://www.prnewswire.com/news-releases/aspen-neuroscience-announces-70-million-series-a-financing-led-by-orbimed-to-advance-development-of-the-first-autologous-neuron-replacement-therapy-to-treat-parkinson-disease-301033098.html
  14. https://www.pmedcast.com/2021/01/13/episode-021-treating-parkinsons-stem-cells-with-professor-jeanne-loring/
  15. https://asia.nikkei.com/Business/Pharmaceuticals/Japanese-stem-cell-treatment-for-Parkinson-s-set-for-US-trials
  16. https://asia.nikkei.com/Business/Pharmaceuticals/Japanese-stem-cell-treatment-for-Parkinson-s-set-for-US-trials
  17. https://www.prnewswire.com/news-releases/exacis-biotherapeutics-develops-mrna-engineered-ipsc-derived-nk-cells-for-difficult-to-treat-tumors-301255010.html
  18. https://www.nature.com/articles/s41563-020-00853-9
  19. https://news.yahoo.com/genetic-engineering-transformed-stem-cells-160702997.html?guccounter=1
  20. https://ipscell.com/2020/12/stem-cells-seed-a-new-thymus-clinical-hope/

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