Landmark IPSC clinical study on hold due to genomic issue

IPSC RPE sheetThe pioneering induced pluripotent stem cell (IPSC) clinical study in Japan led by top stem cell clinical researcher Dr. Masayo Takahashi has been stopped reports the WSJ in Japan. This development is confirmed by other sources and in a PDF report by RIKEN (in Japanese here).

One patient was transplanted in September 2014 with their own IPSC-derived retinal pigment epithelial cells (using an innovative RPE sheet, see image) for treatment of macular degeneration.

The study then moved on to a possible second patient, whose IPSC did not pass a genomic validation step. Reportedly, these IPSC contained a mutation, potentially in a known oncogene, which is a serious concern. Thus, the team decided to at least temporarily suspend the trial pending a possible redesign. The new plan could involve a change in how the IPSC are produced. For example, the team is reportedly considering the possible use of allogeneic IPSC as well, which could come from CiRA (Center for iPS cell Research and Application, Kyoto University).

It remains unclear at this time whether the mutation in the second patient’s IPSC was pre-existing in the patient’s skin cells or if it occurred during the reprogramming process itself. This is a critically important question to resolve. If the mutation was caused by/associated with reprograming then that would be a deeper issue.

Overall, this situation is of course a concern, but it also reflects the very rigorous and appropriate degree of caution that this team was using in validation studies. Notably, the first transplanted patient is apparently doing well.

I hope to learn more details from Dr. Takahashi and will pass that along on the blog when possible. She has also been tweeting about this development (you can follow her at @masayomasayo). Until we learn more it is advisable to take a cautious approach in interpreting this development.

42 thoughts on “Landmark IPSC clinical study on hold due to genomic issue

  1. Thanks for this interesting article
    What does the following sentence mean exactly.
    “Notably, the first transplanted patient is apparently doing well”
    Are there no sight effects? Or is this patient doing better as before?

  2. As far as I am aware, this is purely a safety study and is not expected to result in improvement to visual acuity. I believe the first patient already had significant photoreceptor loss due to AMD and the treatment is unlikely to repair that.

    It is commendable that the team is putting this ongoing info into the public domain. Rarely do you get to see such decisions and accompanying rationale presented almost as it happens – as if we were all invited into the study to observe and discuss. Exciting times and I with them every success.

  3. Thank you for her Twitter account. However, everything is written in Japanese!

    • Twitter will do translation for you…it’s often not such a great translation but still can give you a sense of what is being said.

  4. Takahashi reported at ISSCR that the first patients visual acuity had stabilized but not improved

  5. Paul-
    It’s unlikely that the mutation was caused by reprogramming– mutations arising by culturing cells, both during expansion and during differentiation, have been noted. Not just by us, but here are two of our papers in case someone wants details:

    2011, large scale study:
    2015, in depth study:

    For those with short attention spans, here’s a review: 2014,

    Two more papers are in the works…it’s getting more interesting.


    • Hi Jeanne,
      Definitely good points. Even if the mutation wasn’t reprogramming-specific (i.e. actually caused by reprogramming), it could occur during the manipulations, culturing and expansion of IPSC clones.
      Perhaps instead the mutation was pre-existing.
      I wonder why the team would be so strongly weighing shifting to all allogeneic then though.
      It would be helpful if they provided more clarification such as on the nature of the mutation both in terms of the gene, when they think the mutation arose, etc. Otherwise we are all just left to speculate.

  6. Paul….any update on your original blog. Can you verify that the trial was halted to sort out this unexpected mutation problem? We want to know asap because we want to post an online article following up the info in your blog!

    Andy Coghlan, New Scientist magazine, London
    (tel: ++44207 611 1216,

    PS — We’re asking because we put the WSJ article through Google-translate and it didn’t seem clear to us that the trial was verifiably halted

  7. @Andy
    very good idea to write an article, where and when can we read your article?

      • @Andy, Thanks for linking to your article, which is very informative (note: although as I now mentioned elsewhere, the title and some other language were way over the top and inappropriate). I hope the trial can resume in the near future. While the 6 mutations together in the 2nd patient’s IPSC constitute a concern that must be and clearly is being taken seriously (and should serve as a cautionary experience for other’s intending to use IPSC clinically), the experience of the team and the rigorous validation steps in the study give reason for optimism looking ahead. Paul

  8. Sorry I cannot explain all the situation about the autologous iPS-RPE transplantation in short sentences, so briefly…..
    It is true that a mutation was found in the cells before transplantation into the second patient, and this is something that we took into account when we made the decision to suspend (for the time being) the study, but the main reason for the suspension was the regulatory change.
    The mutated genes were not driver genes for tumor formation and the finding of the mutation was not something that called for a halt of the trial according to the protocol. We are planning to move to allogeneic transplantation because we found in the animal experiments that the iPS-RPE cells cause little or no immune response if the HLA is matched.

  9. @Andy
    What do you think about an article about the exact stem cell application of Rafael Nadal (see several articles on this blog) here. I am looking for the exact details of this treatment, which seems to be successful, because Rafa is back on the center court. Until now, nobody could tell me the exact details of his treatment. Maybe you and your magazine are able to find it out.

  10. @Masayo Takahashi
    Thank you for writing on this blog. I would like to know why do you think allogeneic cells could be more suitable than autologous cells? What is the advantage?
    With autologous cells there won’t be any risk of an immune response at all.
    Thank you in advance

  11. @Andy
    Thank you for your article. I like your magazine and will read it now.
    Please write more articles about stem cells and stem cell applications.

  12. @Masayo Takahashi – thank you for sharing your ideas and news as it happens. It is very educational and encouraging to hear your perspective on the future of stem cell therapy and the lessons of the last years. Also interesting to read your comment about teaching the press about expectations (the interview with Paul). What a challenge!

    @Andy Coghlan – I guess you have to sell copy but I’m not likely to recommend New Scientist with headlines like, “Cancer scare halts pioneering stem-cell trial..”, “Short-lived success” and “Worrying discovery”, when this gives a completely false impression and is a unhelpful considering the openness with which the team is reporting their work. Tabloid journalism. I can recommend the interview with Masayo Takahashi on this blog.

    • @Burt, I have to agree on the language in the New Scientist article being in some cases inflammatory. Both the title and “short-lived success” part in particular strike me as off-base. It’s frustrating.

  13. We are planning allogeneic transplantation, because we can treat several times more cases in the same time period than autologous transplantation with minimum immune response.

  14. The title of the New Scientist’s article “Cancer scare halts pioneering stem-cell trial to cure blindness” is completely wrong.

    • @Masayo,
      I agree about the title of the New Scientist piece being extremely problematic. I apologize for not noticing that yesterday. As Burt also pointed out, some other language in that piece was also inappropriate.

    • @Masayo,
      Could you please help us to understand the regulatory change? Until you mentioned it, I had not heard of this before. It still seems unclear to many people. When did this change happen? Which governmental agency instituted the change? What exactly does the change say?

  15. The important thing is that we prepared a robust safe scheme by using RPE cells. It is not affected very much by genetic changes. The RPE cell is unique.

    The New Scientst’s article omit the part of my comment “but the main reason for the suspension was the regulatory change. The mutated genes were not driver genes for tumor formation and the finding of the mutation was not something that called for a halt of the trial according to the protocol.”

    And the title of it “Cancer scare halts pioneering stem-cell trial to cure blindness” is completely wrong. I am afraid it will cause the public’s fear for stem cell treatment.

    The risk size should be considered from various points of view. Genes, dell types, the disease, the stage of disease, the case situation. Too much emphasis on genes will mislead the progress of regenerative medicine.

  16. I will explain about the regulatory change after the report from ministry of education will come out. It will be within a month.

  17. @Masayo Takahashi
    Thank you so much for answering my question and thank you for your statements. Your stem cell science is very impressive.

  18. Thank you Masayo for your continued engagement. Misleading headlines and editorial highlights can cause incorrect assumptions – more care should be taken given the efforts to safely advance the science for benefit of all.

    Exchange from ISSCR interview on approval requirement of switch to Allo below, as part the regulatory issue…


    “Masayo next patient

    Q: And the next patient?

    MT: We tried, we prepared but decided to go quickly to the allogeneic because the cells are already there from Shinya Yamanaka’s cell line stock. He made the 1st iPS cell line and they have come to our lab.

    Q: Have they been approved as clinical grade by the Japanese regulators?

    MT: Yes but about the protocol, we will apply within this year for approval. We should reapply as it’s allogeneic, different from autologous.”

    New Interview With Masayo Takahashi (高橋 政代) on IPSC Trial: Guest Piece by Michael Cea – Posted on July 7, 2015

  19. Why not use allogeneic RPE from hESC techniques?
    The whole strategy is to get cells that work with safety and replace the damaged cells.

  20. Very interesting work!

    I have a simple question to researcher Masayo Takahashi MD and/or prof. Paul Knopfler:

    what is happening with the old damaged cells/tissues?

    Are they “washed out”/cleaned by the new implanted cells?

    If this the mechanism of cleaning old/damaged cells/tissue, do you know if it is the same for other stem cell therapies for other older damaged organs like kidney, liver, etc.

    Thank you!

    All the best with your work!

  21. Dear all, thanks for your insightful comments on the issues raised in my story. To reflect your concerns, we’ve changed the headline and one of the crossheads in the story. You can read the revised version here:
    Kindest regards to you all, and best wishes to Prof Takahashi with her efforts to move the trial forward
    Andy Coghlan, New Scientist

  22. Dear Mr. Coghian,
    Thank you very much for changing the title. It is very important in this kind of emerging field that media people understand deeply and choose words carefully to avoid unnecessary conflicts.

    Dear Michael,
    This is what I said in the interview.
    I tried to communicate with media people for more than 10 years in Japan to make our project understood deeply in the public. It seems that we should do the same thing with foreign correspondents and try to find good ones.

    • Much appreciated! I look forward to updates on your trial, and will make every effort to accommodate any sensitivities that might arise. Best wishes for a speedy resumption, and every success with the trial. I hope that within the next year or so we have a promising story to tell!!

      All the best
      (PS — I opposed the original headline, but was overruled)

      • @Andy, I appreciate your commenting here and also that the publication made some positive changes to that piece. This difficult situation is a really important story to cover. I wish more media had reported on it.

  23. Dear Paul and Andy:

    Since there is concern about the spin put on this issue, I am posting the email message I sent in response to Andy’s request for comment:

    “Hi Andy:

    Sure. Unfortunately, I don’t know any more than anyone else about this particular situation- I wish I did, because I’m hoping to avoid such problems as we develop our own stem cell therapies.

    There are some things that I know. Most mutations that we can detect by sequencing are benign changes in the genome that happen every day in our own bodies. If the mutations are harmful to the cells themselves, the cells self-destruct -or if they change the cells enough, the immune system goes after them. These are safeguards the body has for keeping us from falling apart. Sorry to seem too philosophical, but we would never reach adulthood if we didn’t have mechanisms to select against bad cells.

    I don’t know what caused the alarm in the macular degeneration trial. I would hope that there were pre-determined criteria for a go/no-go decision, but I don’t know who would have set those criteria. It’s highly unlikely that the mutation of concern was present in the majority of the patient’s cells, because that would have meant that she harbored cancerous cells in her skin. It probably existed as a minor population in the skin cultures, or arose de novo during cell culture and differentiation of the cells.

    It’s important to understand that even mutations in oncogenes and tumor suppressors don’t guarantee that cancer will result. And, epigenetics (silencing or unsilencing of genomic sequences) as well as genome changes need to be analyzed. My lab is trying to do all of this, but, as I’m sure it’s hard to believe, there is no funding for this kind of work.

    The most important information we need to obtain as scientists is what mutations should be considered to be dangerous and which mutations are benign.


    From Andy Coghlan, New Scientist magazine, London, England
    (tel: 011 44207 611 1216)

    Dear Jeanne

    I see you’ve already commented on the iPS trial setback (see link below) following discovery of a potentially oncogenic mutation in the cells prepared for the second patient. Is this a disaster, or are you confident that they can get it back on track? What are the key things they need to find out to be able to resume the trial, do you think? Also, would allogenic skin cells solve it for this patient, if it turned out to be a mutation in his/her own skin cells.

    Be great if you could send a quick thought or two asap today!

    Hope that’s do-able!

    Kindest regards


    • @Jeanne, thanks for sharing this email exchange. It’s helpful as a behind the scenes look and provides interesting context.

  24. Dear Andy,

    (PS — I opposed the original headline, but was overruled)

    I can understand the situation very well. It seems to be happening everywhere. The persons who interviewed directly usually understood very well, but the desk overruled and put sensational titles. I think we scientists should say “it is not good” for raising this kind of new fields. So this time it worked well and I appreciated it.

    We cannot go further without the right understanding of the public.
    And I would like to solve the misunderstanding in the near future.

    • Thanks for your understanding Masayo. I wanted you to know what happened in the hope you would trust me in the future.
      Best of luck with it all


  25. from dauphin

    “The following quote by Takahashi makes sense:

    Quote Originally Posted by Masayo Takahashi
    We are planning allogeneic transplantation, because we can treat several times more cases in the same time period than autologous transplantation with minimum immune response.
    Although the following is quite strange in my opinion:”

    Allogeneic defeats the argument of using IPS vs, hESC …..the question now is what technique give you the best product for the specific disease state….I.E. hESc might be better for RPE but ISPC might be better for RNP cells ….One has to assay fro cell surface , gene expression and cytokine production to know these pathways and protein in the micro-environments …most of this work can and should be done in animal studies and then published

    “Quote Originally Posted by Masayo Takahashi

    The risk size should be considered from various points of view. Genes, dell types, the disease, the stage of disease, the case situation. Too much emphasis on genes will mislead the progress of regenerative medicine.

    That reads a bit like: “too much emphasis on safety will slow progress”, doesn’t it?”

    concerns with safety are the primary goal for the patients well being ……second is the COG to the patients and can it be scale up/ manufactured ? risk have to be mitigated

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