December 5, 2020

The Niche

Knoepfler lab stem cell blog

Overview of IPS cell prospects for clinical impact

Suhas Sakamuri
Author and Knoepfler lab intern, Suhas Sakamuri.

IPS cell research is a growing area of promise for regenerative medicine. These stem cells, also known as iPSCs or more formally as Induced Pluripotent Stem Cells, are engineered cells that are programmed to function the same way as embryonic stem cells. They can be differentiated into possibly any type of cell that is needed for therapeutic purposes.

Since iPSC production was first reported by Shinya Yamanaka using mouse and human cells in 2006 and 2007, respectively, cells from a whole host of species have been successfully reprogrammed. 

From a clinical perspective, the manufacturing process for iPSC cells starts by extracting somatic cells such as skin or blood cells from a patient and culturing them in order to generate larger numbers of cells. Then, these cells will be reprogrammed into IPSCs by introduction of embryonic transcription factors.

After validation, these new iPSCs are harvested and cultured before being injected back into the patient. They can also be used for disease modeling and drug screening too. In this post I cover each of these potential uses.

Current State of IPS cell clinical arena

In terms of understanding the pathology of a disease, iPSC cells are proving to be an invaluable asset. Unlike typical non-pluripotent cells extracted from a participant, which stop growing in a lab after some passages (i.e. they are mortal), iPSC cells keep growing to supply a theoretically unlimited amount of cells to turn into any type of cell needed for a particular study or for transplantation into patients. Researchers tend to prefer lower passage IPS cells because they having a lower probability of having mutations. In 2019, iPSC cells were used for modeling of neurogenesis in Parkinson’s disease, reported here and here.

stem cell polling
Embryonic stem cell polling by Gallup. An increasing fraction of Americans support embryonic stem cell research, now by more than 2-to-1. It’s not clear how the U.S. feels about IPS cell research.

In contrast to human embryonic stem cell production that requires the use of early human embryos and can raise ethical questions for some people, human iPSC cells are made independently of embryos. This origin looks to be helping them gain a wider appeal by avoiding the controversies and issues that have at times accompanied embryonic stem cell research. 

It’s notable, though, that the past debate surrounding embryonic stem cells seems to have greatly abated and recent polling suggests that in some countries like the U.S. there is wider acceptance of human embryonic stem cell research. For example, see the screenshot above of trends in Gallup polling.

IPS Cell Clinical Studies

Since the first report of iPSCs in 2006, how much has this technology advanced at the translational and clinical level? Of course, the pioneering work of Masayo Takahashi for macular degeneration really got things going but there are many more efforts ongoing now.

A recent article published in NPJ Regenerative Medicine does a great job of describing and categorizing the PSC clinical trials found on The NPJ Regenerative Medicine report focused on a subset of 131 studies, finding that the majority of them, 77.1%, were purely observational and did not include the transplantation of any PSC into patients. The remaining 22.9% were interventional. Interestingly, 74.8% of the interventional studies used embryonic stem cells. 

IPS cell Suhas Diagram 1
The global landscape of PSC clinical trials. Deinsberger, et al., NPJ Regenerative Medicine, 2020.

The above diagram from the article does a great job of showing the overall landscape of clinical trials and where they are conducted.

Another figure (below) from the article showcases the major diseases that are being studied in the iPSC clinical trials that were identified.

IPS cell Suhas Diagram 2
The global spectrum of diseases being addressed in pluripotent stem cell clinical trials. Deinsberger, et al., NPJ Regenerative Medicine, 2020.

Cynata, GvHD

A team using Cynata’s CYP-001 iPSC-derived MSC product recently published a Phase 1 trial in Nature Medicine that is important to highlight. The paper, Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study, reported good safety of CYP-001, which was the main outcome measure.  There were also potential indications of positive impact on the course of GvHD, although additional, larger trials are needed to clarify potential efficacy.

Fate Therapeutics, Cancer

In early 2019, Fate Therapeutics got the first iPSC-related IND in the U.S. for their IPSC-derived natural killer cell (NK) product called FT500. Fate’s FT500 is just one of the company’s at least 6 iPSC-derived products under study. This piece this summer includes as update from the company includes a lot more detail on FT500 and their other iPSC work. On Fate’s own website you can learn more about the 6 products including FT516 (click on the different tabs at the top). You can also check out the 2 listings for FT500 here.

Parkinson’s Disease Treatment

Two years ago, a team including Drs. Takayuki Kikuchi and Jun Takahashi produced dopamine precursors from IPS cells. The cells were implanted into a patient suffering from Parkinson’s disease. So far, it has been reported that no major adverse reactions have occurred. They hope to test it on six more patients and to get results by the end of 2020. With the current speed of the trial, it is hoped that it can be sold as a treatment by 2023.

Organ Synthesis and Organogenesis

When thinking of iPSC cells and their ability to be differentiated into any type of cell, using these reprogrammed cells as the basis for trying to bioengineer individual, relatively simple organs makes perfect sense. Dr. Takanori Takebe and his team have gone a step beyond that and managed to use iPSC cells to create multiple complex organs consisting of the liver, bile ducts, and the pancreas all at the same time.

This is a very impressive feat and has great potential to help further understand organogenesis, the process of different organs connecting via tissue boundary interactions. This proves that iPSC cells can be used as a way of observing the organogenesis of a multi-organ structure. Such research including Dr. Takebe’s team found that the gene, HES1, plays a profound role in liver failure in children. Using this information, they are hopeful that future research can be done to find a treatment that can reverse this genetic malfunction. The clinical effect this may have in medicine can be profound in the future by helping doctors understand the correct types of treatments by understanding the underlying genetic and many other complex interactions in organogenesis that cause disorders. There is even hope that this kind of approach may generate human organs for transplantation into sick patients who sometimes spend years awaiting traditional organ transplants. Some patients even die while waiting.

iPSC’s for Disease Modeling

A Nature publication explains the great use of iPSC’s for disease modeling through directed differentiation to develop organoids for various body parts. These organoids are made from WT and mutation iPSC’s. Comparing the healthy and diseased organoids is allowing scientists to understand the physiological effects that the mutations have on the body. The process of drug development can be made much more effective and targeted with the additional information that the modeling provides. 

An example of this can be seen in the study of cardiac organoids that mimic cardiomyopathy through the use of “organ-on-a-chip” technology, which mimics the muscle contractions of the heart. It has been particularly useful in comparing the blood flow with a healthy heart and understanding the complications that arise. This technology is also being researched to study viruses in 3D systems and the effects pathogens have on their hosts.

The use of iPSC’s for disease modeling has a large range of possibilities with the many different organs that it can mimic through organoids. iPSC can potentially revolutionize how many fields in medicine such as oncology, and infectious diseases research diseases and drug development.

Urine as a basis to make iPSC’s

A team managed to find a way of acquiring easily reprogrammable epithelial cells to make iPSC’s from urine samples. They observed that these urine iPSC’s were very easy to differentiate. This method provides a potential alternative method of acquiring iPSC’s that is much less invasive and could be much more effective.

Cancer Vaccine

Professor Joseph Wu and his team at Stanford Medical School have discovered an interesting use of iPSC cells in creating a potential cancer vaccine.  They discovered that injecting reprogrammed iPSC cells in the form of cancer cells back into mice showed significant reduction of their melanoma sizes. The method reportedly generated a significantly increased number of IFN-Y spots, an important cytokine responsible for anti-tumor immunity.  A big advantage to this technique is that it is possible to introduce many different cancers to the immune system simultaneously. 

Conclusions and Future Perspectives

In the context of the long scope of biomedical research, iPSC’s have only recently gained recognition for their rapid improvements in technology and potential contributions to biomedical research and medicine. Many interesting foundations are being laid out for iPSC cell technology. While the field still has relatively few clinical trials compared to other stem cells, iPSC’s have the potential for major clinical impact in the future.

Note: This post is not meant as a comprehensive overview of all IPSC work with clinical relevance.