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!

Sally Temple on adult RPEs for vision impairment, IND, & more

adult RPEsAt the recent RPI stem cell and bioengineering meeting, the Neural Stem Cell Institute’s Sally Temple talked about her group’s intriguing retinal pigmented epithelial cell (RPE) research.

With the broad focus of attention in the world of RPEs mostly on those derived from either human ESC or IPSC, it was exciting to here about the adult RPEs that Temple’s group has isolated and characterized (e.g. see this paper).

Although only about 3% of cells isolated from the human retina turn out to be retinal stem cells, Temple reported that they can be scaled to provide plenty of potential doses (see below).Sally Temple cells

One of the remarkable things about these stem cells is that they can make beautiful RPEs and also perhaps through some kind of EMT, they can generate cells of the mesenchymal lineage (see image below).

They are hoping to have an IND in the next couple years. I’m very curious how the adult RPEs compare to those made from pluripotent stem cells.retinal pigmented epithelial stem cells

I also asked Sally after the meeting to give a big picture perspective on this work:

“My experience in translating the discovery of RPE stem cells towards a therapeutic for age-related macular degeneration is that it is an intensive team effort. You really need to have experts in different aspects of the science, animal modeling, safety testing, regulatory science and clinical disease, both doctors and patients, all working together. Our experience has been amazing, everyone on the team is working so hard to create this new therapeutic. You also need substantial funding, and we have to thank the NYS NYSTEM program for creating this incredible opportunity via their clinical translation program.”

I’m curious what the pluripotent stem cell-derived RPE fans (e.g. Ocata, the IPSC RPE team in Japan led by Masayo Takahashi, etc.) think of this adult RPE approach.

Rensselaer Polytechnic Institute stem cell meeting report

Last week I attended and spoke at a stem cell meeting at Rensselaer Polytechnic Institute (RPI). It was entitled, “Bioengineering and Stem Cell Research”.

It was a great meeting with many interesting talks. Below I write about some of the talks and themes of the meeting. Still to come later this week I will do a second post entirely focused on the exciting RPE work of Sally Temple, who spoke at the meeting.

Mark Noble

One of the major themes of this meeting was, as Mark Noble put it during his talk, the urgent need for greater precision in defining our cells, whether they are stem cells or derivatives of stem cells. A lack of precise cellular identification interferes, Noble said, with comparing data within labs and between labs, patent evaluation, and therapy development.

Noble also asked how we are going to pay for stem cell therapy development, which is a huge often overlooked issue (see slide above from his talk). One of Noble’s innovative ideas is to focus on already FDA approved drugs, providing an effective shortcut to the bedside. This is a potentially very powerful approach if you can find molecules amongst the already approved ones that do what you want.

Mike West of BioTime also spoke at the meeting. He presented about their neat clonal derivative research from ESCs. The numerous determined stem and progenitor derived in this way have more focused differentiation potential that proves very useful and addresses the concern of heterogeneity of cell populations made directly from human ESCs.

The talk of another speaker, Ron Hart from Rutgers, was somewhat of a cautionary tale. His team was working on IPSC made from patients with Ataxia Telangiectasia (A-T). The IPSC had with compound heterozygous mutations in the ATM gene. At some point in the process of studying these cells they found that a certain mutation was lost. It seemed to become WT and the team’s sense is that a spontaneous gene correction event occurred via the otherwise WT sequences of the mutant ATM alleles. It never occurred to me that a heterozygous line could essentially lose a mutation via gene correction. Another possibility that we should all be on the look out for is contamination of one IPSC line with another.

Overall this was an exciting meeting and I don’t even include in that the tornado watch on the second day. Again, stay tuned for an upcoming blog post on Sally’s work on adult RPEs.

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.

Meet the Retina Institute of Japan: translating iPS cells to the clinic

Retina Institute of JapanThe stem cell field is still abuzz about induced pluripotent stem (iPS) cells 7 years after their discovery.

This amazing embryonic stem cell-like cells can be made with no embryo and have the potential for truly patient specific therapies as well as dish-in-a-dish modeling and drug discovery.

How will iPS cells get to patients?

A big player is the Japanese company Institution, Riken.

iPS cells are being commercialized and at the forefront far seems to be the Retina Institute of Japan (RIJ), which appears to be just one (but a leading) commercial arm of Riken’s efforts to translate iPS cells to the bedside and generate income. The image above is from the RIJ homepage and appears to be a human iPS cell colony. Their goal is to use iPS cell-produced retinal pigmented epithelial cells (RPE) to treat macular degeneration.

Still most stem cell researchers do not know about RIJ.

I looked them up and started with their mission statement, getting a translation from my friend Noriko. I think the mission statement is very cool:

On 2/24/2011, we established a company Retinal Japan Institute, with the goal of next generation medicine and drug and instrument development.

” Delivering happiness to the people in the world by bringing iPS cells into clinic” – this is a huge responsibility.
However, we are not afraid of this huge responsibility.
 
The road to the goal will be full of difficulties.
No footprints, maps, nor signs
 
There is no fast track to achieve this goal, and it may take 10 or 20 years.
However, no one can stop us starting the first step toward the goal today.
No one can stop us assembling a team and make efforts toward the goal.
We will start with a small dot, the dots will form a line, then a line will form a large road.
This large road will be filled with joy of patients who benefit from the iPS treatments.
You do not need to hesitate.
Let’s start.
One reason that I like this motto so much is that it is passionate, but also realistic and extolls patience.
I am hopeful, despite earlier concerns that I have expressed, that RIJ will indeed take the time it needs to do the thorough animal safety testing studies that are crucial before making the big jump into studies in humans.
One issue is of course that it has competition. For example, Advanced Cell Technology (ACT; ACTC) has an extremely similar product made from embryonic stem cells that is already well into combined phase I/II FDA-approved clinical trials. However, in the end patient safety has to come first or everybody loses in my opinion.