Good stem cell news as Takahashi IPS Cell Trial to Resume

Masayo TakahashiSome good news today as the pioneering induced pluripotent stem (IPS) cell trial led by Dr. Masayo Takahashi will resume.

This clinical study with a focus on macular degeneration has been on hold for quite some time due to regulatory changes in Japan. There had also been concerns over mutations in the 2nd patient’s IPS cell product.

As previous signs had indicated, the new clinical work will have an allogeneic focus, most likely drawing IPS cells from a bank.

According to a Japan Times article:

For the second trial, the CDB will develop retinal tissues from iPS cells supplied by Kyoto University’s Center for iPS Cell Research and Application, headed by Nobel laureate Shinya Yamanaka, the creator of the pluripotent cells.

Transplants of CDB-developed retinal tissues will be conducted at Kobe City Medical Center General Hospital and Osaka University Hospital.

This is exciting and I’m very curious to see how this clinical work develops.

In 2014, Dr. Takahashi won my Stem Cell Person of the Year Award.

This may also signal a door opening for other IPS cell trials in Japan including one for Parkinson’s Disease by Jun Takahashi.

Historic turning point for IPS cell field in Japan?

As many of you know, the pioneering, first of its kind IPSC clinical study in Japan has been suspended as I first blogged about here. 

In the comments section of that blog post there has been a helpful overall discussion that has involved Dr. Masayo Takahashi, the leader of the trial. It is great that Dr. Takahashi has been participating in this discussion and I commend her for that openness.RPE sheet_pr

This comment stream has been particularly important because the media have only minimally reported on this important development. There have been only a few articles in Japanese (several months ago) and as far as I know only one in English, which was posted in the last day or so in The New Scientist. Unfortunately The New Scientist article, as many have noted here, used an inflammatory title invoking a supposed “cancer scare” and some over-the-top language. Although that article had some bits of important info, the negative bias in the article made it overall not very helpful. Some readers of that article were likely confused by how it was written and the title.

The clinical study in question is for macular degeneration and involves the use of sheets of retinal pigmented epithelial cells (RPE) made from IPSC (e.g. see image above from RIKEN). Several of us have been discussing the suspension of this trial over on Twitter too including Dr. Takahashi (@masayomasayo). Some tweets by the community have been constructive. Others not so much.

Two main possible issues have come up in the discussion of the reasons for the trial stopping: (1) six mutations were detected in the 2nd patient’s IPSC and (2) significant regulatory changes are on the way in Japan that apparently in some way will delimit IPSC research there. Dr. Takahashi has indicated that the latter reason was the dominant factor in their decision to suspend the trial. The fact that the 2nd patient’s IPSC reportedly had six mutations that were not present in the original somatic cells warrants further discussion too. For example, when and how did these mutations arise? To be clear, however, I do not see (based on the information available) that there was a “cancer scare” by any stretch of the imagination as The New Scientist article had indicated.

At some point a restarted version of this study will likely focus on allogeneic use of IPSC perhaps via an IPSC bank being developed by Dr. Shinya Yamanaka. For many years the consensus, most exciting aspect of IPSCs in the field was considered to be their potential for use as the basis for powerful patient-specific autologous therapies. The apparent planned shift to non-autologous clinical use of IPSC in this case raises the question of how it would be superior or substantially different to the use of hESC, other than that making IPSC does not involve the use of a leftover IVF embryo.

This development also raises a 2nd question as to whether there will be a domino effect now of other clinical studies or trials that are in the works using IPSC switching to allogeneic paths as well. In other words, is this a historic, turning point moment for the IPSC field in Japan overall away from an autologous path? Or is the switch here to allogeneic just a one time, one study decision? More info on the regulatory changes is needed to help clarify the answer to this question and the path forward as well.

Hopefully the regulatory body in Japan (Ministry of Education?) that has made or is making the relevant regulatory changes will announce them publicly in detail soon.  If that information is already out there (e.g. in Japanese on the web) perhaps someone can find it and we’ll post it here.

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.

Book Excerpt: Top 4 Stem Cell For-Profit Good Citizen Biotechs

The below is an excerpt from my book, Stem Cells: An Insider’s Guide.

I hope you enjoy this excerpt and the book, which I think is a really good deal at under $27 paperback or under $17 for E-book version.

Having our innovation and ethics too

In the stem cell field you can have it both ways. As a company, you can be ethical and help patients. There are many examples of stem cell-related corporations doing “the right thing” when it comes to developing therapies based on growing stem cells in the lab. Below I discuss a few of these companies (Disclosure: I have no financial interests in these companies, which are listed in alphabetical order).

Advanced Cell Technology

As one example, let me mention a company called “Advanced Cell Technology” or ACT. I would argue that, especially in the last half dozen or so years, the company has been a model citizen in the for-profit stem cell field.ACTC

ACT’s most advanced product in the pipeline toward the clinic is an embryonic stem cell-based therapy for macular degeneration, the leading cause of blindness. ACT grows the embryonic stem cells in culture and differentiates them through a complex process into special cells called retinal pigmented epithelial cells (RPEs). Macular degeneration robs people of their sight because their endogenous RPEs die off. Therefore, the principle behind ACT’s therapy is to replace the endogenous RPEs with exogenous ones. So far, ACT has reported no major negative outcomes from its trials of transplants of embryonic stem cell produced-RPE. I am discussing ACT here because it follows FDA rules and works in an ethical manner to protect patients. It publishes its data and engages patients.

Athersys

Athersys is an adult stem cell company developing allogeneic products to treat a number of important human diseases. The company has five clinical trials listed in the government database. AthersysThe target diseases include stroke, heart attack, blood cancers, obesity, and ulcerative colitis. Their top-line product, MultiStem, is described by the company in one of their clinical trial write-ups as follows:

“MultiStem(r) is a new biological product, manufactured from human stem cells obtained from adult bone marrow or other nonembryonic tissue sources. Factors expressed by MultiStem cells are believed to reduce inflammation and regulate immune system function, protect damaged or injured cells and tissue, promote formation of new blood vessels, and augment tissue repair and healing.”

Athersys has a good reputation in the stem cell field for transparency including regularly publishing their data and following FDA regulations.

Mesoblast

Mesoblast is another good citizen in the stem cell field and has an unusually large number of stem cell products in the pipeline. Their work is based on a type of cell that they call the “Mesenchymal Progenitor Cell” or MPC. Interestingly, while typically progenitor cells have less potency than stem cells, as we discussed earlier in this book, Mesoblast’s MPCs are not your ordinary progenitor cells. 

Mesoblast_Ltd

I recently heard a talk by Dr. Paul Simmons of Mesoblast who reported that MPCs are in fact more potent than MSCs, which is an interesting paradox of nomenclature. Mesoblast is conducting FDA-approved clinical trials for a host of human diseases. I found 9 clinical trials listed for Mesoblast including for conditions as variable as spinal disc injury and heart attacks.

NeuralStem

NeuralStem is a fourth good citizen in the stem cell for-profit world. They are a model citizen for the field when it comes to transparency says Alexey, who I trust on this a great deal, publishing data and even publicly releasing their patient consent form, a rarity in the stem cell field. NeuralStem currently has four clinical trials listed in the database: two on depression, one on spinal cord injury, and one on Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig’s Disease).NeuralStem

The key, positive roles of investors in good-citizen companies

It is important to also highlight the crucial role of investors in making safe, effective, ethical, and compliant stem cell treatments a reality. For-profit stem cell companies including the good citizens of the corporate stem cell world need large amounts of cash to make stem cell-based medicine a reality.

The money comes from investors, who are hoping that some of the exciting stem cell biotech companies become profitable. I know from talking with many of the investors that they are choosing to invest in the stem cell companies not just because they believe that they will be profitable, but also because the stem cell products of those companies will potentially help people suffering from diseases and injuries. I believe that the investors in publicly traded stem cell companies fulfill a key role in accelerating stem cell cures. They tend to be a highly educated, engaged group of people as evidenced by their posts on a website for stem cell investors where I sometimes blog as well.

Investors in privately owned companies can also have positive roles, but I am concerned that in that context the lack of transparency may lead to a more complex, potentially ethically problematic influence.

The main overall challenge in a for-profit setting is to create a business regulatory environment in the stem cell field that enables good actors to succeed.