Yamanaka Interview on Clinical Use of Pluripotent Stem Cells

Dr. Shinya Yamanaka

Dr. Shinya Yamanaka.                                           Photo from CiRA, Kyoto University

I invited Nobel Laureate Shinya Yamanaka to do an interview on the future of clinical translation of induced pluripotent stem cells (iPSC).

He provides some intriguing new insights into the iPSC field and the broader stem cell arena.

PK: The Takahashi Team’s active Clinical Study using iPSCs to make RPEs to treat Macular Degeneration has generated a great deal of excitement. Can you please share your perspectives on the importance of this work and the team involved? 

SY: This is the first study to apply iPSC technology to human care. This is a very important study, because if it succeeds it will show that iPSCs can be safely used in humans and also their potential for cell transplantation treatment. We collaborated with Dr. Masayo Takahashi of RIKEN CDB by evaluating the safety of the iPSCs and iPSC-derived cells that were used for the cell transplantation. She is an excellent researcher, and I am not surprised that her team is the first to have succeeded in this transplant.

PK: Any cutting edge investigational clinical work such as this has some risks. Could you please comment on the potential risks in this iPSC trial? Are there some elements here such as preclinical data, the number of cells used, or the target tissue of the eye that lower risks?

SY: One of the major concerns is whether transplanted cells such as the RPE sheets will cause tumors. In our collaboration with Dr. Masayo Takahashi’s team, we evaluated the safety of iPSCs and iPSC-derived cells by genome and epigenome analysis. While we minimized the risk to a level acceptable for clinical trials, we really cannot confirm how the cells will respond until we actually do experiments with humans, which is why this project is so important. One advantage of treating age-related macular degeneration is that it is easy to detect any abnormalities in the eyes, which is why the disease is a good starting model for iPSC-based treatment.

PK: As the inventor of iPSCs did you imagine 7-8 years ago that a patient in a clinical study in 2014 would already have received an iPSC-based treatment? How was this rapid translation from bench to bedside possible?

SY: I was surprised that after the announcement of human iPSCs in 2007, Dr. Takahashi told me that she would bring iPSC to the bedside within five years. I thought it possible technically speaking, but doubted it could be done so soon, since we needed to improve the technology and get government approval. It took 7 years, which is remarkable considering the work required. Both the accomplishment and the speed at which it was achieved are testaments to Dr. Takahashi’s leadership and her strong team.

The rapid transition is because many bright and passionate people are in the iPSC field. The funding and infrastructure provided by the Japanese government is also a major factor, as these have encouraged excellent scientists to enter the field.

PK: We are also starting to hear more about Dr. Jun Takahashi’s Team’s important work towards using iPSCs to treat Parkinson’s Disease. Can you please tell us more about that?

SY: Prof. Jun Takahashi’s team at CiRA is working on cell therapy for Parkinson’s disease, aiming to transplant iPSC-derived dopaminergic neural progenitor cells into PD patients’ brains. Early results suggest this treatment can be effective, and his team has established the protocol for transplantation. They are now focusing on validating its safety using monkey models. We hope his work will soon reach the operating room within the next few years.

PK: What other clinical applications of iPSC technology are in the works and that might begin clinical studies in the next few years?

SY: There are two major clinical applications of iPSCs, namely regenerative medicine and drug discovery. CiRA has a number of researchers working on either or both. For regenerative medicine, Prof. Koji Eto at CiRA is working on generating platelets via iPSCs, and we expect this will also proceed to clinical research in a few years. Besides work at CiRA, a team at Keio University has a plan to conduct clinical research on patients with acute spinal cord injury in four to five years, while Osaka University and Keio University hope to transplant iPSC-derived cardiac myocytes into patients with heart diseases within a few years. CiRA is collaborating with these teams as well.

Regarding drug discovery, you may have heard recently of CiRA’s Prof. Noriyuki Tsumaki’s paper about statins effects on bone growth, which was published online in Nature last month.

PK: Some in the media are taking about a certain tension between clinical iPSC work in Japan and clinical iPSC work in the US. Do you believe such a tension exists and if so, why? What does it mean for the iPSC field overall?

SY: I am not sure what “tension” means. I understand that both competition and collaboration exist between the US and Japan.

PK: How do you view hESCs today? Are there hESC clinical trials or potential applications that are of particular interest? What is your view of the argument by some that hESC are no longer needed?

SY: Human ESC was a great discovery for regenerative medicine and also instrumental to the discovery of iPSC and the type of medical treatments we are aiming to apply iPSC. At the same time, the ethical issues that hESC possess mean that as iPSC technology improves, hESC will be less needed. Still, iPSC is a new technology, and its safety and efficacy still needs to be confirmed. In addition, there may be some therapies for which hESC are better than iPSC. Thus, I think basic and clinical research of hESC is also important and should be done in parallel with iPSC research.

PK: What excites you most about the stem cell/regenerative medicine field right now today?

SY: I am excited about the possible number of people treated with iPSCs. This field has great potential to provide treatments for currently incurable diseases. Hopefully, within 5 years, we will refer to Dr. Masayo Takahashi’s AMD work as just one of many patient studies using iPSCs.

PK: Where do you see the iPSC field and the broader stem cell field in say 5-10 years?

SY: It is pretty amazing how much it has changed in the past years, so predicting the next 5-10 years is very difficult. I certainly hope we will see more diseases being treated with iPSC and related technologies such as direct reprogramming. I also hope that iPSC will be used more widely and routinely in drug development.

PK: What advice would you give to young scientists today who are excited about a career in stem cells/regenerative medicine?

SY: Through biomedical research, you could help thousands of patients in the future. Stem cells provide unprecedented opportunities in stem cell therapy and drug development. Biology of stem cells itself is extremely interesting. I hope many young scientists will enter to this field.

Stem Cell Pioneer Masayo Takahashi Interview on iPS cells, clinical studies, & more

Masayo TakahashiIn the interview below I talk with Dr. Masayo Takahashi, who is leading a team conducting the first ever in-human clinical study based on iPS cells. The work began with patient enrollment on Aug. 1, 2013 in Japan.

1. Can you tell us a bit about your background? As an M.D./Ph.D. and ophthalmologist do you also see patients in addition to doing research? How did you first get interested in stem cells? Are your interests primarily in iPS cells?

Yes, I have outpatient clinics in two hospitals next to RIKEN and see the patients with retinal degeneration.

I encountered the concept of stem cells at Prof. Gage’s lab in the Salk Institute in 1995. At that time I decided to make treatment for retinal degenerative diseases using stem cells. So I applied the concept of stem cells for retinal transplantation for the first time (Mol. Cell. Neuroscience 1998)

After several years of research in Japan I moved to ES cells because I realized that somatic stem cells cannot be expand enough for many patients as a standard treatment. With help of Dr. Sasai we made retinal pigment epithelial cells from ES cells ( PNAS 2002). When I saw the pigmented clumps of cells in the dish that Dr. Sasai asked me to evaluate in 2000,  I was confident that RPE will be the first ES-derived cell used in a successful clinical treatment and it will be industrialized.  I reported the first treatment of animal model using primate ES cells (Invest. Ophthalmol. Vis. Sci. 2004)

But I hesitated to develop a treatment with ES cells because I myself as an ophthalmologist did not want to use immune suppressant for the elder patients with tiny eye diseases. So it was natural that I immediately moved to iPS cells in 2005 when I heard about iPS cells before the article came out.

2. As the leader of the pioneering first ever in human study of an iPS cell-based therapy, can you fill us in on the process that went into making the trial a reality beginning with patient enrollment on Aug. 1? How long ago did you start preparing for the trial? What steps did you have to go through? Do you think some of your pre-clinical data may be published soon?

As reported in the Invest. Ophthalmol. Vis. Sci 2004, we had Proof of Concept with ES-derived RPE and ready to go into the preparation for the clinical trial. So that we started preclinical study with human iPS cells from 2007. Then we confirmed that the hiPS-RPE have the suitable characteristics for the clinical use in the aspect of quality, quantity, consistency and safety. These data was finally accepted in the Stem Cell Report.

3. Can you tell us how many patients have been enrolled so far? Are autologous iPS cells from any enrolled patients already being made? For the average patient how long do you predict it will take from their enrollment to their treatment?

We cannot announce the enrollment because of the confidentiality of the patients.

The surgery will be held 10-12 months after enrollment.

4. What method is being used or will be used to make the iPS cells? Sendai Virus for example or another approach? Why did you pick this method?

We decided to use a plasmid (episomal vector) according to the discussion with CiRA

5. How will you validate the new iPS cells from each patient? Will you, for example, do a whole range of tests such as genomics, gene expression, epigenetics, in vitro differentiation, and in vivo behavior in animal models? Do such validation tests present challenges such as being costly and time consuming? Why are they important?

We will choose suitable iPS lines severely from genomics, morphology, stem cell markers and karyotype. CiRA will help us.  We have technique for good RPE cell differentiation from 100% of iPS cell lines we choose so far.

We did in vivo efficacy test in the preclinical research but we will not do it again in the clinical research. On the other hand, we will do the tumorigenicity test for each patient’s iPS-RPE at least for the first several patients’ iPS-RPE.

They are very much  time and money consuming. However, it is important to evaluate thoroughly because it will be the first trial.

6. It would be very helpful if you could explain to us the difference between a clinical study and a clinical trial? I understand you are starting with a clinical study. How does that work and assuming all goes well with this study, what would be the next step? A clinical trial?

A clinical study is under the medical practitioner’s law. It is a unique system in Japan that is like a practitioner’s exemption.

Clinical trial is the ordinary system in the world under the pharmaceutical law. The pharmaceutical law has been changed to be more regenerative medicine friendly, so that in the next clinical application we will use the ‘clinical trial’ track.

Our first auto-transplantation of iPS-RPE sheets might become ‘an advanced therapy’ (that is also unique system in Japan). I do not think it will go under clinical trial because it is too expensive to be a commercialized standard treatment.

7. Many patients have asked me how many years it might take before we have iPS cell-based therapies for macular degeneration are fully approved and in common use. What’s your take on that?

It depends on the regulation in each country. However, it will not become in common use before 10 years. ( In Japan, by chance,  it will be 5 years or so.)

8. In the long run, do you think patients can be treated via iPS cell-approaches entirely in an autologous fashion or is it important to establish iPS cell banks for potential matching and allogeneic use? 

To make the treatment as a standard one, the cost should be decreased. In that sense allogeneic transplantation will be necessary. Also we should think about how to bring the cost down of autologous transplantation.

9. Advanced Cell Technology is conducting a similar kind of clinical approach but using hESC. Can you comment on that and how your study and theirs are similar or different?

We will treat wet type Age related macular degeneration (AMD) with RPE sheets, while ACT are treating dry type AMD with cell suspension.

10. What excites you most about stem cells and where do you see the field in general say in 5-10 years?

With ES or iPS cells, the regenerative medicine will go into the industrialized stage at least in the field of RPE.

The effect of regenerative medicine will not depend on the donor cells but depend on the host condition and the surgery skill. We should think of it as medical treatments. Furthermore, the regenerative medicine therapies, especially retinal regenerative medicine, will be completed with rehabilitation (low vision care), so we should think about total medical system.

As for the stem cells, the potential of evaluating patients’ iPS-derived retinal cells is exciting. We have never evaluated patients’ retinal cells.