In the interview below I talk with Dr. Masayo Takahashi, who is leading a team conducting the first ever in-human clinical study based on iPS cells. The work began with patient enrollment on Aug. 1, 2013 in Japan.
1. Can you tell us a bit about your background? As an M.D./Ph.D. and ophthalmologist do you also see patients in addition to doing research? How did you first get interested in stem cells? Are your interests primarily in iPS cells?
Yes, I have outpatient clinics in two hospitals next to RIKEN and see the patients with retinal degeneration.
I encountered the concept of stem cells at Prof. Gage’s lab in the Salk Institute in 1995. At that time I decided to make treatment for retinal degenerative diseases using stem cells. So I applied the concept of stem cells for retinal transplantation for the first time (Mol. Cell. Neuroscience 1998)
After several years of research in Japan I moved to ES cells because I realized that somatic stem cells cannot be expand enough for many patients as a standard treatment. With help of Dr. Sasai we made retinal pigment epithelial cells from ES cells ( PNAS 2002). When I saw the pigmented clumps of cells in the dish that Dr. Sasai asked me to evaluate in 2000, I was confident that RPE will be the first ES-derived cell used in a successful clinical treatment and it will be industrialized. I reported the first treatment of animal model using primate ES cells (Invest. Ophthalmol. Vis. Sci. 2004)
But I hesitated to develop a treatment with ES cells because I myself as an ophthalmologist did not want to use immune suppressant for the elder patients with tiny eye diseases. So it was natural that I immediately moved to iPS cells in 2005 when I heard about iPS cells before the article came out.
2. As the leader of the pioneering first ever in human study of an iPS cell-based therapy, can you fill us in on the process that went into making the trial a reality beginning with patient enrollment on Aug. 1? How long ago did you start preparing for the trial? What steps did you have to go through? Do you think some of your pre-clinical data may be published soon?
As reported in the Invest. Ophthalmol. Vis. Sci 2004, we had Proof of Concept with ES-derived RPE and ready to go into the preparation for the clinical trial. So that we started preclinical study with human iPS cells from 2007. Then we confirmed that the hiPS-RPE have the suitable characteristics for the clinical use in the aspect of quality, quantity, consistency and safety. These data was finally accepted in the Stem Cell Report.
3. Can you tell us how many patients have been enrolled so far? Are autologous iPS cells from any enrolled patients already being made? For the average patient how long do you predict it will take from their enrollment to their treatment?
We cannot announce the enrollment because of the confidentiality of the patients.
The surgery will be held 10-12 months after enrollment.
4. What method is being used or will be used to make the iPS cells? Sendai Virus for example or another approach? Why did you pick this method?
We decided to use a plasmid (episomal vector) according to the discussion with CiRA
5. How will you validate the new iPS cells from each patient? Will you, for example, do a whole range of tests such as genomics, gene expression, epigenetics, in vitro differentiation, and in vivo behavior in animal models? Do such validation tests present challenges such as being costly and time consuming? Why are they important?
We will choose suitable iPS lines severely from genomics, morphology, stem cell markers and karyotype. CiRA will help us. We have technique for good RPE cell differentiation from 100% of iPS cell lines we choose so far.
We did in vivo efficacy test in the preclinical research but we will not do it again in the clinical research. On the other hand, we will do the tumorigenicity test for each patient’s iPS-RPE at least for the first several patients’ iPS-RPE.
They are very much time and money consuming. However, it is important to evaluate thoroughly because it will be the first trial.
6. It would be very helpful if you could explain to us the difference between a clinical study and a clinical trial? I understand you are starting with a clinical study. How does that work and assuming all goes well with this study, what would be the next step? A clinical trial?
A clinical study is under the medical practitioner’s law. It is a unique system in Japan that is like a practitioner’s exemption.
Clinical trial is the ordinary system in the world under the pharmaceutical law. The pharmaceutical law has been changed to be more regenerative medicine friendly, so that in the next clinical application we will use the ‘clinical trial’ track.
Our first auto-transplantation of iPS-RPE sheets might become ‘an advanced therapy’ (that is also unique system in Japan). I do not think it will go under clinical trial because it is too expensive to be a commercialized standard treatment.
7. Many patients have asked me how many years it might take before we have iPS cell-based therapies for macular degeneration are fully approved and in common use. What’s your take on that?
It depends on the regulation in each country. However, it will not become in common use before 10 years. ( In Japan, by chance, it will be 5 years or so.)
8. In the long run, do you think patients can be treated via iPS cell-approaches entirely in an autologous fashion or is it important to establish iPS cell banks for potential matching and allogeneic use?
To make the treatment as a standard one, the cost should be decreased. In that sense allogeneic transplantation will be necessary. Also we should think about how to bring the cost down of autologous transplantation.
9. Advanced Cell Technology is conducting a similar kind of clinical approach but using hESC. Can you comment on that and how your study and theirs are similar or different?
We will treat wet type Age related macular degeneration (AMD) with RPE sheets, while ACT are treating dry type AMD with cell suspension.
10. What excites you most about stem cells and where do you see the field in general say in 5-10 years?
With ES or iPS cells, the regenerative medicine will go into the industrialized stage at least in the field of RPE.
The effect of regenerative medicine will not depend on the donor cells but depend on the host condition and the surgery skill. We should think of it as medical treatments. Furthermore, the regenerative medicine therapies, especially retinal regenerative medicine, will be completed with rehabilitation (low vision care), so we should think about total medical system.
As for the stem cells, the potential of evaluating patients’ iPS-derived retinal cells is exciting. We have never evaluated patients’ retinal cells.