Takahashi team IPS cell vision paper marks major stem cell milestone

Ring the bell for a stem cell milestone.

There’s been a whole lot of commotion about the NEJM article yesterday documenting the experiences of three women with macular degeneration who were blinded by non-FDA approved stem cell eye injections of fat stem cells at a business in Florida, but in the same issue of the journal there also was some encouraging stem cell news that came in the form of essentially a mirror image of the bad news paper. We can call it the “stem cell good news-bad news” issue of NEJM.

Takahashi IPS transplant

Mandai, et al. NEJM 2017 Figure 1C

The good news was the publication of the first paper on clinical use of IPS cell-derivatives in a human patient. A big milestone. This groundbreaking manuscript comes from the pioneering team in Japan led by stem cell scholar Dr. Masayo Takahashi. I’ve written extensively in the past about the work of Takahashi and her team with IPS cells, and she received my Stem Cell Person of the Year Award back in 2014.

In the new paper they detail their data from the clinical study using sheets of retinal pigmented epithelial cells (RPEs) made from IPS cells in this case derived from the patient herself for autologous use. Remarkably in Figure 1C (above) you can see the actual transplanted RPE sheet in the eye of the patient (see dark area indicated by white arrow). The most encouraging part of this study was that the patient’s vision remained stable (rather than declining as expected) following the treatment. Was that due to the transplant? We can’t be sure.

Also, this is just a beginning as it is just one patient, but it is very exciting and represents a big milestone for the IPS cell and broader stem cell field, providing real hope for patients with vision loss along with parallel ESC-based clinical trial work as well.

This paper contrasts so much with the report from the other one in the same issue on the terrible outcomes from the stem cell clinic’s use of fat stem cells in the eye. While the use of fat stem cells themselves is highly questionable in my view for this application, the biggest differences between the two approaches is that the Takahashi team work was extremely rigorous, careful, based on extensive preclinical studies, had governmental approval, and was in essence science-based clinical medicine.

For instance, the Takahashi team was appropriately cautious with Patient 2 since the cells exhibited some genomic changes. At least in part for that reason, moving forward this clinical work will primarily focus on allogeneic use of IPS cells via an IPS cell bank being developed by Shinya Yamanaka.

We can also look to other future IPS cell-based trials coming on-line including for Parkinson’s Disease and other conditions, which are likely to be allogeneic as well in Japan, but probably autologous here in the U.S.

I love a good stem cell milestone!

Stem Cell Person of the Year 2014: Masayo Takahashi (高橋 政代)

Masayo Takahashi

Dr. Masayo Takahashi,  Asahi photo

Congratulations to Masayo Takahashi (高橋 政代), MD, PhD, the winner of the 2014 Stem Cell Person of the Year Award.

Dr. Takahashi received this award including the $2,000 prize for her exceptional achievements in stem cell research in 2014. She was selected as the winner from a stellar group of top 12 finalists this year.

Takahashi leads a team doing high-risk, high reward research that is conducting the first induced pluripotent stem cell (IPSC) clinical study in humans ever. I interviewed Takahashi at the beginning of this year and you can learn more about her research and vision for the future from reading that interviewMonkey stem cell RPEs

The Takahashi team clinical study is intended to examine the safety of a human retinal pigmented epithelial cell (RPE) product made from each patients’ own IPSCs. You can see at right RPEs produced by her team from monkey pluripotent stem cells.

In an astonishing feat of speedy clinical translation, Takahashi’s team transplanted its first macular degeneration patient recently on September 12, only 7 years after human IPSCs were first ever published. The usual timeline for such translation would be 20 years. In that regard, in a recent interview I did with him, Nobel Laureate Shinya Yamanaka had this to say of Takahashi and her work:

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.

Her achievements extend beyond this year to an outstanding long-term track record in vision research including a very impressive track record of highly-cited publications. Takahashi is physician scientist, who is a faculty member and Project Leader at the Laboratory of Retinal Regeneration at the CDB at RIKEN. Some of her nominators for the Stem Cell Person of the Year Award described her as a “transformative” and “courageous” stem cell scientist. Below you can see a TEDx talk from just a few months ago by Takahashi explaining her work.

Takahashi joins previous Stem Cell Person of the Year Award recipients Roman Reed and Elena Cattaneo as outside-the-box thinkers who to take risks to make outstanding new developments in the arena of stem cell research with the goal of helping others.

More about the Stem Cell Person of the Year Award. I fund this prize myself as a way of giving back to the stem cell community and recognizing transformative people who take risks to help others. It is to my knowledge the only annual, international science-related prize personally funded by a professor.

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.

As iPS cell studies in humans approach, accessible relevant pre-clinical data remains minimal

When are iPS cell-based therapies ready to be tested in actual people?

It’s the million or perhaps even billion dollar question of today in the stem cell field.

I realize that perhaps it is also a dangerous question, politically-speaking, for me to ask in a public forum, but patient lives as well as potentially the progress of the entire iPS cell field are at stake.

So someone needs to start an open discussion about this topic. People are certainly talking about it behind the scenes asking questions such as:

  • Are iPS cells being raced too fast to the clinic?
  • Who will be the “winner” in terms of commercializing iPS cells?
  • Will the iPS cell field find itself in a gene-therapy, Jesse Gelsinger kind of situation soon?

Tragically, Gelsinger and a few other patients died from what one might say was a gene therapy treatment that was not ready for prime time and from a side effect not anticipated by researchers based on animal studies. The gene therapy field was crippled for two decades.

Masayo Takahashi ISSCR talk

We all want to get stem cell-based medicines to patients who need them as soon as possible, but there is such a thing as going too quickly.

There are quite a number of teams around the world working to make iPS cell-based therapies a reality in humans, but the team at the forefront is in Japan led by Dr. Masayo Takahashi.

How strong are the Japanese team’s pre-clinical data on the iPS cell-based retinal pigmented epithelial cell (RPE) therapy for macular degeneration (MD), the leading cause of blindness in the world?

No data has been published so it is a tough question to answer.

Six months ago I asked whether things were moving too fast on moving iPS cells into people? 

It is an even more apt question today in April 2013 as the first ever transplantation of the first iPS cell therapy into human patients seems ever more imminent in Japan. The proposed study has already been approved by some regulators and is awaiting approval from one last regulatory body in Japan.

Even though the pre-clinical data have not been published on this study so far, there is at least a small window into that world.

Takahashi gave a lecture at the ISSCR 2012 Annual Meeting on her lab’s pre-clinical work on iPS cell-derived RPEs for treating MD. ISSCR made the video of Takahashi’s very important talk available on the web here, but only to ISSCR members. Fortunately I watched it before its run was supposed to end.

The talk was outstanding, just not enough to support in human iPS cell studies in the near future to my way of thinking.

As mentioned above, none of the data have been published yet as well. Interestingly, three leaders in the stem cell field that I queried all essentially told me the same thing when I mentioned the lack of published pre-clinical data on safety of transplanted iPS cell-based therapies using clinically relevant transplantation paradigms:

“They do not have to publish their data and in fact why would they when that would give their competitors an advantage?”

There is a dilemma here. On the one hand, data are viewed by for-profit companies and scientists as proprietary and valuable assets. In the iPS cell field those assets could be measured in billions of dollars. On the other hand, openness protects patients and the field more generally. How do we find the right balance?

One other earlier published study by a different team was encouraging on safety based on studies in mice, but far from strong enough to support studies in humans.

Of course prior publication of pre-clinical data is not specifically required for regulatory approval to start a clinical study, but given the historic nature of what could be the first ever in human iPS cell study, it would be extremely wise in my opinion for teams to publish their work first.

Since the data is in fact not published yet, how strong were the data in Takahashi’s talk?

In her ISSCR seminar given 10 months ago, Takahashi presented some safety data from mice on the RPEs, but not from larger animals such as monkeys. To be clear, larger animal studies are not also not required, but this is an important distinction since larger animals are sometimes better models for humans and also because there were some anecdotal reports that said she had in fact presented larger animal pre-clinical safety data at the ISSCR meeting.

The only large animal data I saw in the web-broadcast of her talk was that an autologous iPS cell-based transplant into monkeys survived and there was no inflammation, but I believe that she later mentioned that this was only done on 1 monkey. Allogeneic iPS cell-based transplant in a monkey was rejected.

From murine safety studies of the iPS cell-derived, purified RPE, Takahashi reported that no tumors were observed using RPE made from 3 different human iPS cell lines. There are some major limitations to how far one can go with this data though.

Three key limitations of these safety studies come to mind:

  • The studies were relatively short-term, only going out to ~6 months.
  • The data presented were only on 5-7 mice, a very low number per parental iPS cell line.
  • The safety testing that was presented consisted only of subcutaneous teratoma assays (assuming I understood this correctly from the talk) and not eye transplant safety data.

My understanding from Geron’s and ACT’s experience at the FDA here in the US is that the short-term nature of this iPS cell safety data along with very low animal numbers and lack of a clinically-relevant transplantation paradigm would be far from satisfying regulators here in the US that human studies should begin. Geron used thousands of rodents, while ACT used hundreds. Follow up was far longer than 6 months in some studies. Both teratoma studies as well as studies using the relevant transplantation modality (e.g. in the eye and spinal cord) were conducted.

Of course the proposed study would not take place in the US so the point is moot from a regulatory standpoint, but it still is illustrative of how minimal the data supporting the study seems to be at least from what is publicly available.

Much more data might and probably does exist, but remain private. 

Indeed, it is probable that the Takahashi team and/or affiliated for-profit teams (the latter being a key point and more on that in future posts) have more data now and/or beyond what was presented at ISSCR 10 months ago. That is my hope. If so, I encourage them to publish it all. It does not have to go into Nature or Cell Stem Cell. Just get the data out there. It is certain to be a high-impact paper regardless of the journal.

Unless there are a lot more, longer-term studies (e.g. 1 year or even longer) done on many more animals (e.g. 100s) yielding equally encouraging safety results specifically on transplants in the retina (not just sub-Q teratoma assays), I am deeply concerned as to whether the field is really ready to make the jump to transplanting iPS cell-based therapies into people any time soon.

I realize that the regulatory system in Japan is different in terms of the process for studying potential medical therapies. Takahashi is proposing a clinical study, which is perhaps more akin to a Phase 0 here in the US and to be distinguished in Japan from a clinical trial, which might come later.

But in any case the bottom line is that  patients (and the field) would be put at risk unless there is far more rigorous pre-clinical animal data.

The field has to hope that the data presented at ISSCR 2012 were just the tip of the iceberg and that much more thorough and compelling data exists below the surface. Further, it is not just the Japanese team, but also many others that are moving quickly to get iPS cell-based therapies into humans for a variety of conditions…..how strong are pre-clinical data?

Who knows. They remain generally unpublished and unavailable for informed review by anyone but regulators.

I hope the iPS cell-based therapies come to fruition as safe and effective for blindness and other diseases, which would be tremendous advances for medicine, but let’s not kid ourselves: the risks are substantial and a lack openness just increases risk further in my opinion.