Masayo Takahashi (高橋 政代) on IPSC Trial for Macular Degeneration
By Michael Cea
Stem Cell Analyst & Advocate
(editor’s note: piece was originally posted on Michael’s blog here; follow Michael on Twitter @msemporda)
Masayo Takahashi interview
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.
As most everyone is aware, the first iteration of the program, for advanced Wet age-related macular degeneration (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.”
Before 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.
Communication and social media
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.”
Cell choice
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.
Disease focus
Q: What is your current disease state target?
MT: Advanced Wet age-related macular degeneration (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.
A wonderful interview, full of detail, rationale and personal drive. The study is a textbook for teaching clinical stem cell science (and makes my job easier as a teacher) in a field where there are as yet no textbooks.
Thanks to all involved – looking forward to the next one.
Yes. I would like to see some answers about that second patient as well.
Thank you Masayo for your feedback and outreach.
Paul can you edit out the “overseas” in the Healios section. Thx.
Cheers
Thank you for putting this.
One point misunderstood is that Healios will do clinical trial in Japan after 2017 or so. They are thinking a clinical trial in US but we do not know when.
Connecting to NIH and Dr. Ali’s group is a little bit strong words. They just exchange the information. Healios is in contact with many other researchers in US and Europe.
I would like to make some comments about the second case in the other article when I will have enough time.
Thank you, Masayo, for your comment and the clarifications.
If you have time could you please tell us a bit more about what happened with the IPSC from the 2nd patient? What was the nature of the (oncogene?) mutation? Was it pre-existing in the patient’s somatic cells or appeared later? Anything else we should know? Many people have been asking me and are eager to know more on this important situation. I understand it is a sensitive situation, but some brief facts could go a long way toward clarifying the situation and stopping people from speculating.
Paul,
We can preselect the HLA type of iPSCs, but not of hESCs.
It’s rare for people in the US to be homozygous for multiple HLA types, but less rare in Japan. If we were to build such a bank here, we would ask for volunteers to provide blood for HLA typing under IRB approval, and when we found a person homozygous for one or more of the HLA types, we’d arrange to make iPSCs.
The ideal person would be homozygous for ALL of the major HLA types, and their HLA types would be common in our population. I’ve found a couple of homozygotes for one HLA locus in our ethic diversity bank, but never a person homozygous at more than one of the loci.
It’s more complicated than this, of course. Heterozygotes would be fine if the donor and recipient carried the same HLA alleles.
While embryonic stem cells are unlikely to provide a match for anyone, it would be worth checking the available lines.
Hi Jeanne,
I suppose in theory we can preselect HLA types of hESC too via making NT-hESC a la Mitalipov and the other 2 groups that successfully did NT. Still making hIPSC is far simpler.
Paul
Thanks for this- I heard Dr. Takahashi’s talk, but this interview adds a great deal to the story.
One very, very important point: the advantages of iPSCs for cell replacement therapy is that they are exactly matched to the patient (autologous), so rejection is not a problem. Dr. Yamanaka is developing a collection of iPSC lines that are homozygous for specific HLA genetic sequences; mismatch of HLA antigens is the primary cause transplant rejection.
It is important to note that development of an HLA-matched iPSC bank that covers a large proportion of the population (for allogeneic transplants) is far more feasible in Japan than it is in the US. We are a very diverse population in the US, far more ethnically diverse than Japan. While I think it would be great to produce a similar HLA-matched bank in the US, there is no funding for it, as there is in Japan, and it would need to be much, much larger to match a significant part of our population.
The main point I want to make is that at this time there are no iPSC banks in the US equivalent to Japan’s, so there are no viable alternatives to patient-specific (autologous) iPSCs if we want to avoid rejection. This doesn’t mean that we won’t someday have these alternatives- we just don’t have them now.
Thanks for the comment, Jeanne. These are great points. Isn’t another alternative the allogeneic use of hESC? I’m not sure I see how allogeneic use of IPSC would be any better than using hESC. Thoughts?