New Interview With Masayo Takahashi (高橋 政代) on IPSC Trial: Guest Piece by Michael Cea

By Michael Cea
Stem Cell Analyst & Advocate
(editor’s note: piece was originally posted on Michael’s blog here; follow Michael on Twitter @msemporda)

 

Having followed closely the developments in programs using pluripotent based therapeutics I was fortunate during ISSCR2015 to have the opportunity to sit down with Dr Masayo Takahashi to discuss her pioneering efforts to translate Shinya Yamanaka’s groundbreaking iPS technology for debilitating retinal conditions.Masayo Takahashi

As most everyone is aware, the first iteration of the program, for advanced Wet AMD, has entered the clinic and been safely administered to the first patient – a milestone achievement for the field, which has been widely covered by the media, especially in Japan. However, as I learned first hand, this first step is but a part of a comprehensive strategy to address most retinal diseases by way of various cultured cell transplantation methods, depending on the patient condition – including suspension therapies and multi-layered organoid developed tissue. This was best described by Masayo “what I have said to the Japanese regulators is that ideally we need all cell types – sheets, suspensions, auto, allo – and the surgeons will choose which to use for each patient.”

Monkey stem cell RPEsBefore relaying the key segments of the interview, I wanted to express some thoughts of how practical and committed to the patient Masayo is. Her clinical practice is at the very heart of her professional vision – to bring relief to those that come to her for help. Disappointment again and again in not being able to help drives her passion for new therapies. She is both confident and open to the process that has already taken more than a decade and a half of her research. The goal being, in time, to have all the tools necessary to deliver on the promise to her patients and fulfill on that hope, that is very real and apparent today – something she couldn’t point to just a few short years ago. Her new message is very clear now “visual impairment is not as bad as they think and you can change that world – so there is hope – yes.”

Cheers

Interview:

Q: There is a lot of hype in the field how have you addressed that?

MT: When I started to do the regenerative medicine work the media broadcast our efforts and many patients came and they expected I could help them. But 10 years ago I was very nervous because after hearing the news they were disappointed in front of me so I started to talk to the media and educate. Every month we worked with media so gradually within this period they learned and suppressed their expectations so in Japan the hype isn’t so high anymore.

Q: Does the Internet makes things easier for patients to understand?

MT: People who can connect with the Internet can understand but the older people still don’t have access to the Internet and rely on the newspaper and TV but sometimes they’re informed wrongly as a result so I still struggle.

Q: Is that due to the technical language and complexity of the science?

MT: Common sense is different from the medical reality but the regenerative medicine area is very focused so we can use the media to inform the public correctly. Regenerative medicine won’t cure everything but if you think in a different way you can do many things. The “hope” should be the correct one. People need to learn the way of thinking of the scientists – in Japan people are very clever and gradually they have understood. So if you teach correctly they can understand gradually. It’s important to relay the correct information. Media sometimes tries to simplify as a need or belief in the communication method yet they lose the true message. Stem cells are a specific area with many unknowns – yes – it’s like a “black box.”

Q: You started using ES neuronal cells then moved to iPS and retinal cells

MT: Yes, a little background. I started in 2000 with ES cells and proved in mid-2000 using primate ES cells that we could treat some retinal diseases but we hesitated to move to the clinical stage because the risk of immune rejection. By that time iPS cells came out and I was very happy as I knew the last hurdle would be solved w/ iPS cells so we immediately started research using those cells and after 5 to 6 years of translational research in preclinical studies we started the 1st patient clinical application last September and we will judge the safety and effect 1 year later this September. We announced mid-term results in March and so far we don’t observe any immune rejection without any immunosuppression, which we expected as a result of using autologous iPS cells.

There was a famous paper in the journal Nature that the autologous iPS cells invoked immune rejection in a mouse model but I think the research design wasn’t very good. They transplanted kind of a tumor which would be rejected – not the iPS cells but the tumor.

Q: Was the surgery difficult for the lady (1st patient)?

MT: Yes the surgery was the most risky part. We were worried a little but the procedure was successful with no adverse events so far.

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.

Q: Will this line be available to others?

MT: Shinya Yamanaka will distribute to various centers with one of the institutions being mine. So there will be a Spinal Cord Injury protocol, maybe the Parkinson’s disease trial will go to an allogeneic protocol, the hematopoietic (platelets) will also. So the various protocols will use that cell stock.

Q: Japan is moving very quickly, is that of concern in the community or is that in your mind appropriate?

MT: Most patients are supportive but some people worry we move too fast but really we prepared, labored and accumulated the data and the people who don’t know the whole data usually say you have the risk – that’s very stressful. So actually we don’t care what they say because they don’t know. Maybe it’s a social balance.

Q: Are you taking the trials also outside of your home market?

MT: In the near future. We made a start-up company, Healios, they made an IPO last week, they plan to do a clinical trial in 2 or 3 years time in the US as they need the time to apply the protocol.

Q: I’d like to get your opinion on the use of a monolayer versus the selection of a suspension protocol.

MT: The people who don’t know the disease think the big sheet is the best but there are many, various situations with the disease, various stages, various lesion sizes, so some patients need a large sheet. Ours is 1 x 3mm, people in the US are preparing a 3 x 5mm sheet, so some people don’t need such a big sheet and earlier stage patients don’t require a big incision, so cell suspension is more feasible.

Q: What is your current disease state target?

MT: Advanced Wet AMD and we pull out the neovascular tissue, so a big defect of RPE, and cell sheets are appropriate but if the neovascular damage isn’t large we don’t want to cut and therefore cell suspension is better.

Q: The market is fragmented – is there a synergy with other programs?

MT: The regenerative medicine area is different than the small molecules, it’s more adaptable, so the judgment should return to the clinical scene and not the big pharma. The clinical reality will determine application and the Japanese government knows very well about this issue and we cooperated to make the new law. The Ministry of Health accepted that regenerative medicine is different than small molecules and that all is needed is a small number of patients to get approval, which is a great advance, a revolution.

Q: Is safety sufficient in a small population study?

MT: Of course the accumulation of the animal data needs to be reconfirmed by 10 or so patients for safety but the statistical significance of the efficacy needs more patients to prove the probable efficacy. Companies can sell the products based on smaller numbers so we don’t need big big pharma for promoting regenerative medicine. Companies can sell but they must register and prove efficacy within 7 years with regular exams. Success will be a collaboration between regulatory and academia with insurance reimbursement playing a commercial role which is incredible and kind of a risky law. The background of that is that academia promoted the regenerative medicine mainly so we cooperate very tightly with government and will decide where to provide treatment after approval with rules later.

Q: Do you plan enhanced cell products?

MT: Manipulated cells can work better, yes. So far natural cells are the most feasible, as regulators don’t like manipulated cells or “supercells.” In future but for now natural cells are good.

Q: Can you speak to the adult cell types?

MT: MSCs are safe. iPS/ES are hard to control so are limited to institutes that can maintain them/control them properly but the industrialization for a standard treatment iPS/ES is very good because we can have one lot otherwise many donors and always a lot of changes so that’s not very good industrially. In the future the ES & iPS cells people can control will be the way to industrialize and standardize treatment.

Q: What are your future plans / next steps?

MT: Our next steps are to have combined stem cell sheets – not only RPE but RPE with Photoreceptors and perhaps the vessel layer. Like a dream in our institute, that has a very high developmental biology focus, we talk about the whole retina with blood vessels and will try to deliver the entire retina for retinal disease conditions that destroy all the layers. For now we are working on monolayers, suspension, photoreceptors, combined layers and ganglion etc with 2016 for the allo, 2017 for the Healios suspension and 2018 for the photoreceptors.

Q: Are you collaborating with other institutions – is that part of your plan, UCL for example?

MT: We are not actually collaborating. We have a communication and information exchange, like a think tank. We know how they promote and we are doing very well. We don’t have to hide. They use similar technology adapted from our work. The aim is to make a standard treatment.

Q: Is ownership not an issue?

For the company it’s an issue – I don’t care. Patients don’t care. Healios is very good and they are in contact with the NIH group and the Ali group (UCL) – maybe they collect good procedures from the world.

Q: Are companies in Japan are looking at this sector as a team approach – does this help?

MT: Yes, society of regenerative medicine companies in Japan are maybe 100 companies now under the F.I.R.M association. Fuji, industry, pharma – all diverse companies. Not as a Keiretsu but more an association. Companies are now interested unlike 5 or 6 years ago. I told many companies to help us but they didn’t in the beginning but now they do. The government has helped a lot having supported the industry 10 years ago but they see the reality now as we have the clinical application.

Q: How do you see yourself, as a leader, role model – is there pressure?

MT: Shinya Yamanaka is like an Emperor now – everyone adores him. About the pressure, we have accumulated the data so I don’t fear anything. I have a scheme for 10 years plus and a plan. I know all – from the cells, the pluripotency, genes, animals, disease, patients and social and no worries only a process to move along. There are some against us but if I listen to their talks I’m not convinced by them, I mean persuaded, something wrong in their logic. As a role model – maybe I should behave myself! Patients happiness is what I believe – not papers or money, not interested. Patients first, outpatient clinic is very important to me.

Q: How do you view Lucentis/Eylea?

MT: Wonderful – we saw AMD 25 years ago and there was nothing at all. So we just explained the disease as incurable for 10 years but finally it came out, it was wonderful. We knew AMD very well and knew Lucentis wouldn’t cure everything. The treated patient had 10 injections before surgery and her condition deteriorated from 0.3 to less than 0.1 even though she had the available treatment, so we stabilized her visual acuity with radical treatment without any injection.

By way of disclosure: I have no conflict of interest, financial relationship with anyone or company mentioned in this article.

Review of Biotech/Translational Talks #ISSCR2015: StemCells Inc, Semma, ViaCyte, & Le Blanc

By Heather Main

The path to the clinic is a slow and arduous activity, frustrating not only to the researcher and patient, but investors. Successful clinical translation of technologies requires a balance of science, streamlined translation and funding. To develop fantastic science and then realise the most important components cannot be adapted to the clinical environment is as disastrous as having a great product but no cash to get it past the post. The fruitful interaction of researchers, companies and clinics will save a lot of pain in streamlining technologies to patients. Thus, it was nice to see an ISSCR 2015 plenary session on stem cell therapies including companies StemCells, Inc. and ViaCyte, Inc. The topics were a good spread of autologous and allogeneic cell sources as well as therapies directed at inflammation and immune reactions versus integrative cell replacement technologies.stemcellsinc-logo

StemCells, Inc. presented progress in clinical trials with allogeneic neural stem cells in brain, spinal cord and eye disorders. As is the reality for companies giving talks some data and beautiful pictures is not disclosed. Though there were no revolutionary data sets on efficacy, what was clear was that grafts could persist 1.5 years post removal of immunosuppression (this was determined with HLA-mismatch begging the development of a Shinya Yamanaka style allogeneic HLA cell bank). It should not be a surprise that there were no amazing efficacy leaps in these first trials. There would be a lot of luck in getting the right cell, the right dose and the right transplantation method in the first go. Even the development of reliable measures of graft behaviour and efficacy will take time to develop and standardise.

Semma TherapeuticsDoug Melton was clear to state that they “haven’t (just) done an academic study”. That while they are not yet in the clinic and even though they present a more classical academic study, showing a complex defined differentiation and detailed functional analyses, that they recognise the importance of not just talking the talk but walking the walk. Doug presented their in-vitro beta-cell body technology that show functional characteristics equivalent to, if not better than, cadaveric islets. They were able to upscale this technology and are now on the prowl for encapsulation technologies to move into the clinical space, which will happen through their new start-up Semma Therapeutics.

ViaCyte New LogoIt’s always nice to hear an Aussie accent ;), giving additional benefits to listening to Alan Robins present the progress of ViaCyte in clinical trials of their pancreatic progenitor and encapsulation technologies. Following on from Doug, Alan made a couple of comments to assure the audience that there was a lot of vigorous science behind their technology, the curse of not being able to disclose and thus somewhat unfairly being seen as less careful. The ViaCyte technology is based on the major phase of expansion in pluripotent cells followed by mass differentiation and subsequent encapsulation. Interestingly in their pre-clinical animals studies the grafts were able to regulate insulin levels at the standard human blood concentrations, indicating not only functionality but also species specific functionality.

Katarina Le BlancKatarina Le Blanc presented her work on MSCs for GVHD, diabetes and vocal cord scarring. Somewhat disappointingly I heard the comments of someone leaving this talk with the all too common disregard that MSC technologies are inferior to pluripotent technologies rather than recognising them as complementary technologies. Katarina showed epithelial cell death and inflammatory markers were reduced with maximal effect at 3 weeks after IV injection for GVHD, even though they also prove that IV infused cells have mostly disappeared already at 3 days post infusion. She also showed that while coagulation and complement cascades are activated in response to IV infusion of MSCs blood clotting is not a common occurrence. The risk of clotting was cell number, dose and passage number dependent, which is a little scary when many autologous therapy clinics do not standardise the cell number they IV inject.

It’s great to see both academics and companies being recognised as the drivers of cellular therapies. Working in a stem cell company myself, I was surprised 2 years in a row to see talks from academics about skeletal muscle differentiation protocols that do not come close to our technology. It’s somewhat understandable that when it is not possible to disclose a lot of details of your research, the companies are often not taken seriously and are relegated to paid presentations during the lunch break. It is fantastic however, to see positive movement in reputable exposure for the companies attempting to drive research to patients.

Overview of Yamanaka Talk at #ISSCR2015 by Heather Main

Heather_MainISSCR day one

By Heather Main

The day of plenary is the most enjoyable in my view. You don’t need to make the choice between sessions and the judgement on the viability of shifting sessions versus staying put and listening to the slightly less relevant.

ISSCR 2015 plenary was, as to be expected, full of the big names, the affectionately known Rusty (Fred Gage), Jonas Frisen (one of the smartest MD PhDs I have ever met) and of course Shinya Yamanaka. In deciding which talk I wanted to highlight it is somewhat cliché to go for the Nobel Prize winner but I just can’t help it, he is just such a great guy.

I first met Shinya at Karolinska Institutet, Stockholm, Sweden, when he was giving a presentation (no doubt an interview for his Nobel Prize). In association with this trip he was interviewed in our lab space where he divulged that he got into research as he didn’t think he was a very good orthopaedic surgeon, he wanted to do something where he could help people!

So, I was very pleased to see that his ISSCR 2015 talk was divided into 3 sections;

  • immune matching of pluripotent cells
  • differentiation and purification of desired cells types
  • pre-clinical testing of stem cell therapies

What this tells me is that Shinya is truly devoted to helping people. That he is not just thinking about the first step or the last step of stem cell therapies but the entire process, each step as important as the next and the previous. It is not enough that he has a Nobel Prize and could spend the rest of his career studying the mechanisms of reprogramming, he wants to drive his technology to the patients. What a star!

The first part of the talk outlined his work into HLA haplotype matching with regard to homozygous individuals. With a current Japanese focus, just one donor homozygous for the most common HLA haplotype would be sufficient to provide immune matched cells to 10% of the Japanese population. 10 homozygous donors with other common haplotypes would cover 50% of the population and 140 homozygous donors would cover 90%. With 1:1000 individuals showing a homozygous phenotype AT LEAST 140,000 individuals would need to be HLA screened, with this number falling drastically short on the fact that a specific repertoire of HLA haplotypes would be needed. So Shinya and his team are scanning the blood donor and cord blood bank stocks to find their golden donors. A huge task, with huge reward.

For differentiation and sorting Shinya’s team have developed a method called miRNA switch. The technique is mainly aimed at those cell types for which we do not have good cell surface markers for FACS sorting. Basically expression of two fluorescent proteins indicates transfected cells, which upon differentiation to the desired cell type, will lose expression of one of the fluorescent indicators under the control of a cell type specific miRNA. These single positive cells can then be sorted or selected with chemical resistance. Simple and elegant though may require significantly larger numbers of cells, dependant on transfection efficiency.

Finally, my favourite iPSC master showed data from a pre-clinical study into Parkinson’s Disease transplantation of Corin+ dopaminergic neurons. For this section Shinya was very careful to acknowledge his collaborator Professor Jun Takahashi, and continued through the section to present the work as ‘he did’ rather than ‘I did’ or ‘we did’. In the study they were able to show that sorted iPSC derived Corin+ dopaminergic neurons transplanted into monkey brain gave functional recovery of Parkinson’s Disease and survived for at least one year without a reduction in graft size and without tumor formation. Interestingly, whether the original iPSC were from diseased or non-affected individuals, similar rescue was seen, arguing for autologous therapies from the diseased individual. These results were setting up for the exciting step of testing these human cells in human clinical trials beginning within the next 2 years.

While Shinya may be the big name, his humility and genuine desire to make a change in the lives of patients is a great inspiration. His continued dedication to the cause in light of his earth shattering appearance onto the stem cell stage is a testament to a great guy. Japan is definitely the space to watch for a dedication to stem cell therapies (including liberal regulatory standards), and I’m sure along with Shinya they will continue to drive the field forwards both at the basic and clinical level.

Top 10 Insider Trends on Stem Cells to Look Out for at ISSCR 2015 Stockholm

isscr meetingThe annual ISSCR meeting has started in Stockholm.

This is always a great annual meeting both for the science and for connecting with people including new friends and colleagues as well as old friends.

Another element to the meeting is the insider conversations in the halls, restaurants, and bars that tell a behind the scenes story of the stem cell field.

Below are my top 10 things to look for that might be discussed over a beer or coffee this year. Also be sure to check out the wonderful guide to Stockholm from Heather Main and if you are there at the meeting enter our stem cell contests to win up to $100.

  • Clinics make an appearance? It’s a long shot, but I keep wondering if some of the stem cell clinic folks will show up at ISSCR some day to try to legitimize themselves even if they don’t speak, etc. Maybe they’ll sneak in with some posters or even just attend to make some connections. Unlikely, but if it happened could prove very interesting.
  • I’ll be curious if the Hanna-Silva feud of a sorts continues persist over ground state pluripotency, MBD3 and NuRD.
  • Does anyone still believe in VSELs?  A scandal is still smoldering there.
  • Anybody know what happened to Vacanti and the assumed to exist Brigham & Women’s/Harvard investigation over STAP cells? Last year in Vancouver at ISSCR STAP cells were one of the hottest topics.
  • Will Mitalipov continue to assert that NT-hESC are better than IPSC after the more recent paper (on which he was an author seemed to show otherwise)? More broadly will the SCNT/human therapeutic cloning folks continue to claim a clear path to the bedside?
  • Any news on Masayo Takahashi’s IPSC trial? More preliminary data?. I’m excited to see how that goes.
  • I keep hoping also that more biotechs will present at ISSCR and be given plenary talks.
  • Is ethics/policy given sufficient attention at the meeting?
  • Will CRISPR-Cas9 editing of stem cells be the talk of the meeting? The explosive trend of this amazing gene editing technology in science overall has really gripped everyone’s attention.
  • How many reports of clinical trial data will be given? Sometimes in the past ISSCR meetings have had a sizable tilt towards basic science. Could that be changing?

ISSCR 2015 Stockholm Contests $100 in Prizes

Amazon gift cardI wish I was going to be with all you who are attending the ISSCR Annual Meeting in Stockholm coming up in a week or so, but this year the schedule just doesn’t work.

I’ll try to be there in spirit.

For those of you attending, I do have something fun though and a chance to win some money.

I’m inviting attendees of ISSCR to submit entries in two contests: (1) guest blog posts and (2) pictures or videos from the meeting itself or from Stockholm.

Submit your entries to me by email: knoepfler@ucdavis.edu. For videos, if large file size is an issue you can send me a DropBox or similar link.

The best quest blog post submitted to me will win a $50 Amazon gift card. You can submit more than one as well as long as it is on a different topic. The more interesting, timely and well-written the piece, the more likely it will win.

The top photo or video from the meeting submitted to me will also win a $50 Amazon gift card. I’m strongly encouraging people to submit videos (not taken of ISSCR talks). Such videos could be of scientists discussing stuff over coffee, beer, etc., interviews, videos of Stockholm, etc. Of course anyone in the photo or video needs to give permission for its use.

If I’m wowed by multiple awesome guest blog posts or photos/videos by different people, I may give more than one prize each for blog posts and photos. On the other hand if I don’t get excellent submission, it is possible that no one will win. I hope the latter does not happen.

Rules

Anyone can enter. Entries must be submitted before the meeting ends. The more timely the submission (e.g. guest blog post on talk sent to me within 12 hours of the talk) the better your odds.

If you blog about a talk at ISSCR that someone gave please get their permission if you intend to include mentions of unpublished data.

The blog post cannot be more than 300 words. Photos in blog posts are encouraged (you must have taken it yourself/have the copyright or have permission).

For the separate photo/video entries, you must have taken the photo or video yourself/have copyright.

All entries may be posted on this blog and by submitting yours you agree to that. Entries may be edited if they are posted.

I will be the judge of the winner and decisions are final.

The prizes are $50 Amazon gift cards in USD that will be received electronically.