Adverse event in IPS cell (ips細胞) trial for vision loss in Japan: initial perspectives

Takahashi IPS transplant
Mandai, et al. NEJM 2017 Figure 1C
Takahashi IPS transplant
Mandai, et al. NEJM 2017 Figure 1C

A team of researchers at RIKEN and Kobe City Medical Center reported at a press conference today a serious adverse event in a clinical trial participant receiving an induced pluripotent stem cell (IPS cell)-based therapy for vision loss.

According to Japan Times and Yahoo! Japan (in Japanese), the patient in question in the IPS cell trial for macular degeneration developed a problem with his eye following the cell transplant. From Yahoo! Japan:

“The patient had an operation on Monday to remove pre-retinal membrane, deemed to be the cause of retinal edema, as the team was unable to improve the symptoms despite the administration of a steroid and anti-vascular endothelial growth factor medication.”

You can see an example of an experimental IPS cell-based transplant of RPEs in the team’s important paper from last year above.

The team leader, Dr. Masayo Takahashi indicated in a press conference that:

“We cannot deny the causal correlation with iPS cells,” Masayo Takahashi, a researcher at Riken who heads the team, said at a news conference.

Takahashi said the symptom “falls into the category of serious cases,” as it requires hospital admission for treatment, but that it is “neither a matter of great urgency nor life-threatening.”

I’m not clear if the IPS cell-derived retinal pigmented epithelial (RPE) cells grew or assembled into this “pre-retinal membrane” or it was more related to the injection protocol itself, but the words “causal correlation with iPS cells” suggests they played a role. Update: However, a translation of the Japanese article now suggests the opposite, that perhaps the cells themselves were not an issue:

“Riken project leader, Masayo Takahashi told that she considers the cause of adverse event the surgical method used for cell transplantation, not iPSC itself.”

It’s reassuring that Dr. Takahashi also said the incident should not interfere with the future of the trial:

“She said the incident should not affect the future process of the clinical study of transplantations of iPS-derived retinal cells in patients with severe eye diseases.”

I’m trying to better understand what happened to cause the problem, but need more information to have a better sense of what the implications might be. A quick Internet search of “pre-retinal membrane” suggests it can be due to scarring of the outer surface of the retina.

Notably, Japan’s regenerative medicine law mandates reporting of such adverse events:

“The team made the announcement in accordance with the law requiring medical institutions to report to the Minister of Health, Labor and Welfare a patient’s illness or worsening condition suspected to have been caused by regenerative medical techniques.”

In the past, a different iteration of the IPS cells for vision loss study in Japan was halted reportedly due to regulatory changes and potentially because a patient’s IPS cells had some mutations. Japan’s IPS cell efforts have switched gears in recent years to a more allogeneic (stem cells from other people rather than from yourself, which is called autologous) focus.

As there are more and more stem cell trials of various kinds, adverse events are to be expected, should be reported as this one was, and with proper controls can be understood in terms of risks as products navigate the process.

This all goes to show that stem cell-based clinical trials are more of a non-linear marathon than a sprint from points A to B, whether the clonal work is based on adult, embryonic or IPS cells.

If I hear from Dr. Takahashi on more specifics of what happened and why or get more information another way I’ll update this post or do a new one to follow up.

2 Comments


  1. Not sure if readers are familiar with the complicated surgical procedure involved in the administration of this RPE cell sheet in the sub-retinal space. It’s a couple of degrees more involved than the hESC RPE sub-retinal bleb protocol used for the cell suspension technique in the Dry AMD/Stargardt disease clinical trials (which had a number of adverse events, including a case of epiretinal membrane). http://www.sciencedirect.com/science/article/pii/S0140673614613763. Of note here perhaps, cell sheets have a history of folding/wrinkling > http://www.sciencedirect.com/science/article/pii/S0142961208008399

    Also generally there are often adverse complications in a Pars Plana Vitrectomy, which is used to access the retina in these operations – https://www.ncbi.nlm.nih.gov/pubmed/20008722 (see Tables).

    I’m glad to see there was an update added to your piece regarding the assessment by Masayo regarding the probable cause of the event. However, additional follow-up/clarification on the surgical risks of the procedure and patient/post-op information in relation to the prior condition of the patient’s eye and the complications would be warranted given the nature of such a public disclosure.

    With regard to iPSCs derived cell therapies there is no indication to-date that they are not safe. This is backed up by extensive pre-clinical studies and the ongoing human proof-of-concept trials. Obviously certain treatment protocols are less invasive surgically – such as systemic administration, versus sub-retinal eye or brain surgery…

    Cheers


  2. Well, this is what I get for looking for updates… ugh. There are no words for how much I hope this does not delay the trials. I guess the positive thing to get out of this is that it likely may not have had anything to do with the cells themselves, and I agree that with this type of surgery and any adverse condition that the patient may have had beforehand, these kinds of complications have every chance of happening. PLEASE, please follow up with any available further information ASAP. I know that you’re very busy, but there are so many people waiting and hoping and praying for results here. And ss usual, I can promise that if I do win Powerball, this blog will be lavishly funded!! 😉

    (P.S.: Hi msemsorda! It’s Cathy Danielson under a different account.)

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