Patients talk stem cells. The FDA listens.

By Jeanne Loring

Last Tuesday I visited the FDA headquarters in Maryland, for a meeting called Public Meeting on Patient-Focused Drug Development for Huntington’s and Parkinson’s Diseases. The FDA holds about 6 meetings on different diseases each year, inviting patients and advocates to speak while a panel of FDA directors listens. The FDA representatives at this meeting included Billy Dunn and Eric Bastings, (Director, and Deputy Director, respectively, Division of Neurology Products [DNP], Office of New Drugs), Susanne Goldstein (Medical officer, DNP), and Theresa Mullin (Director, Office of Strategic Programs). All of these people are from the Center for Drug Evaluation and Research (CDER), which is the branch of the FDA responsible for evaluating new drugs. Biological therapies, including stem cell therapies, are evaluated by another branch of the FDA, the Center for Biologics Evaluation and Research (CBER). These CDER members will not be directly examining stem cell therapies, but it’s still useful for them to be aware of them – and they may have friends at CBER.

Summit for Stem CellsThe morning session, on Huntington’s disease, was both disheartening and inspiring: disheartening to hear about how horrible the disease is, and how it affects families – inspiring to see how hope still lives among the stricken and their family members. There are no treatments- none. HD is caused by a trinucleotide repeat in an essential gene that changes its function; the man next to me introduced himself as “a 43 CAG”, which means that he has 43 repeats of the trinucleotide CAG, enough to cause moderate pathological symptoms. His son, he said, is a 46.

Jenifer RaubThe afternoon was for Parkinson’s disease. I was there with two members of the Summit for Stem Cell Foundation, which is supporting development of a patient-specific stem cell therapy in my lab in collaboration with Dr. Melissa Houser at Scripps Clinic: Sherrie Gould, a nurse practitioner who treats PD patients is the heart of the foundation, and Jenifer Raub (pictured in photo from the meeting at left from Jeanne Loring) is a patient who speaks eloquently about the impact of the disease on her and her family. Jenifer was one of 5 patients who were chosen to speak directly to the FDA on a panel about therapies. If you want to add your own comments, the FDA is taking comments until November 23 at this link:!documentDetail;D=FDA-2012-N-0967-0747 .

Jenifer’s words will appear in the transcript and are far more meaningful than anything I could say- here is some of what she said:

“My Name is Jenifer Raub. …I have Parkinson’s disease….Every day is a struggle with the ups and downs of Parkinsonian symptoms and at the end of each day I am exhausted and frustrated.

I never know what tomorrow brings. Another day filled with the same unpredictability – Can I stand? How much pain will there be? How long will the medications that are working today continue to do so???

Acceptance of this instability is often frustrating. I heard a lot of frustration in persons here today…I have days I’m reminded of the fact that the medicines I take will not be effective forever. Parkinson’s disease is progressive. Those are the days I look at my children and grandchildren and wonder: How long will the medications be effective? How much time do I have?

My life has a new definition of “normal”. Parkinson’s disease has redefined my family, friends and marital relationships. There is NO cure for Parkinson’s disease today.

And, yes, I have looked for alternate treatments for my condition. I do not want to be dependent on medications for the remainder of my life… I strongly believe that there is great promise in the NEAR future for stem cell therapy for the treatment of Parkinson’s disease -specifically induced pluripotent stem cells, which are patient specific and DNA matched…Stem cell therapy in Parkinson’s disease has a 30 year history. Decades ago studies were done using fetal cells. Those participating in those studies are now dying of natural causes and the dopamine cells at the time of death were still viable! Fast forward 30 years – today a simple skin cell can be made into a pluripotent stem cell and consequently a dopamine producing neuron…. [Summit for Stem Cell hopes to file an application with the FDA in 22-36 months. I know the risks and side effects of the medications I take. I know the risks of stem cell therapy. I am willing to take the risk rather than acquiesce to Parkinson’s disease. Let me – Let US have the right to take the risk and the right to choose HOW we fight the symptoms of Parkinson’s.

I fight EVERY day to move. I am fighting for a life with my family…I want a future with the simple joy of being with my husband, my children and my grandchildren. I want to see my grandchildren graduate college. I want to attend their weddings and I want to meet their children and kiss their foreheads.

Time is limited for someone with Parkinson’s.

MY time is limited.

Give me a chance to choose. Give all of us a choice. I would like to ask the FDA to consider supporting and furthering this new and revolutionary field of regenerative medicine that will change therapies and treatment for not only Parkinson’s disease but for so many diseases that there is NO cure for today.

Thank you for your time…I appreciate you listening to me…”

Michael Cea’s conversation with Jeanne Loring: frank views on all things stem cell

By Michael Cea

Jeanne Loring of the Scripps Research Institute in La Jolla, California kindly sat down with me at the ISSCR annual meeting for a broad discussion of her history, views on the field and developments in the science.

I found Jeanne a refreshing character, as I did a number of others I was fortunate to meet in Sweden. Her style I can only best describe as natural. It must be the Southern California air or something but there is a definite quality of relaxed confidence about her. I liked her a lot and hope to have the opportunity to meet her again sometime – perhaps at the birth of her “to be” Northern White Rhino! If she invites me 🙂 that would be something.

The format of the interview was free flowing and what was clear to me from her long standing scientific focus and deep knowledge of the sector was it takes determination and a varied set of skills to maintain one’s position in today’s fast paced world of cutting edge science and more so even to successfully translate that to the clinic.Jeanne Loring

Kudos to Jeanne for her efforts to continue the fight to bring forward a therapy for Parkinson’s after near on 30 years and for her passion to help our planet’s most endangered.

Hope you find the interview interesting, as much as I enjoyed it.



M: Tell me a little about your background

JL:  I was trained in embryology and neurobiology, I studied neural crest cells, which are actually stem cells and I was fascinated by them. Then when I finished graduate school I got a job as an assistant professor at the University of California Davis and I then realized I could either teach or do research but not both. There were not enough hours in my day, so I took the opportunity to join a biotech company in California called Hana Biologics. There were lots of companies around in 1987. I joined specifically because they were planning a stem cell therapy for Parkinson’s disease. I was getting a little bit tired of generating just knowledge. I wanted to generate practical knowledge, which made me a little bit different from most biologists at the time.


Lewy Body characteristic of Parkinson’s

M: Was that motivated by personal experience?

JL: No, I didn’t know anybody who was sick at all; it was just I wanted to have more impact than just writing papers. I wanted to do something more important. When you go into biotech there’s a high probability that you’ll not be at the same job for more than 5 years. I didn’t know that at the time but I’ve learned it now- it’s good for learning how to survive. The first company I went to work for (in the late 1980’s) was developing a cell therapy for Parkinson’s disease, but there were no pluripotent stem cells yet so we were using fetal cells -trying to expand them. That was the heyday of the fetal transplants for Parkinson’s disease and it was clear they were working for some people, so why couldn’t we take fetal cells and expand them and treat more patients?

M: I attended the pre-meeting symposium @ Karolinska on the aging brain. The eye and brain are related of course but the brain is less accessible.

Lewy Body characteristic of Parkinson’s. Image from Wikipedia.

JL:  The eye is accessible; therefore it is a good testing ground for therapies. Once you put things in the brain you pretty much don’t know what’s happened until the person dies.

M:  Why did the fetal work not continue?

JL: There were two main efforts – Andreas Bjorklund of Karolinska/Lund and two groups in the US who were funded by the NIH to do clinical trials. I think the people in Sweden will always argue that they had a better success rate. The researchers In the US were required to, or decided to, do a double blind clinical trial to assess placebo effects.

M: And surgery?

JL: Yes, they did sham surgeries for the double blind trial.

M: Isn’t that unethical?

JL:  I would never do it but it was the expectation of the NIH-funded trial. The patients did have the promise of treatment if they were part of the control group.

M: You mean opening them up again?

JL:  Yes, but the people who routinely do brain surgery don’t take this issue as seriously as I do, and they know what they’re doing.

To continue, the problem was that maybe 25%-30% of the patients, depending on the study, had an adverse effect that was quite dramatic, called dyskinesia. When they got the cells they had Parkinson’s disease, which was treatable with L-Dopa, but then after they had the cells they started having uncontrollable events, like the opposite of that sort of frozen kind of characteristic of people with Parkinson’s disease. They had to be treated separately and it had obviously been caused by the transplant. The question was…

M: Why?

JL: Exactly. The fetal cell therapies stopped in about 2003. I remember I was at the Society of Neuroscience meeting when the results were discussed and everyone in the room was saying… we can’t do this anymore.

M: But 75% of the patients were…

JL: Were either not helped or they were helped for the rest of their lives and went off drugs. So it was clearly a spectacular therapy.

M: This was so early, late 80s early 90s, wouldn’t you think that with more push in the science?

JL: Everything sort of dropped off the map at that stage and people just didn’t pursue it anymore.

M: Was it ethically charged?

JL: The question was: do you want to do something to people that has a clear probability of an adverse effect? Parkinson’s disease is not a life threatening disease.

M: It is a debilitating disease.

JL: Yes, it is a debilitating disease.

M: I have a relative that has Parkinson’s, in my wife’s family, and it’s not just the disease it’s what it does to you aside from that. Your whole spinal column changes and that makes everything more painful and difficult.

JL: Everything is more challenging and you can never predict whether you’re going to have a good time or bad time today or this morning or afternoon. I have a friend in Texas who has Parkinson’s disease – I talk to him on the phone every once in a while and it has to be at a particular time of day. Otherwise I can’t understand him at all.

M: Devastating disease, all the neuronal diseases are devastating.

JL: That was the whole basis for my Parkinson’s disease focus, after there was a resurgence in interest when human pluripotent stem cells were made. We can turn these cells into real dopamine neurons and do just what we want with quality control.

M: This was the question I had at the brain symposium, why wouldn’t you test the neural stem cells themselves as a method of action and let them stimulate the environment.

JL: People have tried that. There was a whole interval where people were trying to treat Parkinson’s with cells that were not dopamine neurons. Actually it damaged the field because it didn’t work and turned organizations like the Michael J. Fox foundation, an organization that had supported it, against cell therapy entirely. They’re not funding cell therapy now.

M: Were those stem cell originated?

JL: No, this was all before pluripotent stem cells were available. They were either adult cells or fetal derived stem cells, and they didn’t become dopaminergic neurons.

M: Isn’t there a big difference in terms of your understanding of the pluripotent sources in terms of that?

JL: Of course. There’s a huge difference. The cells you get from an adult or fetus have not been successfully turned into the same neuronal cell type that dies in Parkinson’s. They don’t seem to be able to.

M: So what about the pluripotent neural stem cells?

JL: Neural stem cells from brain aren’t pluripotent- they can’t develop into all cell types. We use pluripotent stem cells to make neural stem cells, which we then turn into dopamine neurons.

M: Ok

JL: So my next job, because fetal dopamine neuron precursor cells couldn’t be expanded, was to work at a company called GenPharm. This was in the early 90s and we were doing gene knockouts and deriving mouse embryonic stem cells so I got to be at the beginning of one field and the beginning of another field. That company lasted about five years.

M: What technology did you use?

JL: Using homologous recombination, which was a brand new idea at the. Mario Capecchi, who was a scientific advisor to the company, won a Nobel Prize for it in 2007. I like being in the situation where the technology I’m using wins Nobel prizes for people. I kind of think that validates it. We could just about do anything. We could knock-out genes and we could change genes. This was all pre Crispr-Cas, which is the way people are doing it now. So that was early days for that as well.

I made a lot of mouse embryonic stem cell lines. This was the same time as Austin Smith and Rudolf Jaenisch were using, making and knocking-out genes in mouse embryonic stem cells. That’s where our histories all overlapped; we were all doing this in the early 90s, although I was at a company, and they were academics. It was a spectacular five years and we did a lot of amazing work. The work I did then is still some of the most highly cited work that I have ever done. It was really pioneering and it was fun. Then after that company failed (most of them do), I moved on to a company called Incyte Genomics. This was at the peak of the human genome sequencing era, which started around the mid-90s. I worked at Incyte for around 5 years learning how sequencing worked.

M: Uncovering the map

JL: Yes, and the technology was evolving very fast at that time. So I now had three things I knew well – the Parkinson’s neural cell transplant idea, embryonic stem cells and now genomics/DNA.

M: This all was at the same time as the other groups but your work went unheralded?

JL:  It was not a big deal- if you’re going to be heralded you have to stick in one field for a long time. My approach has been to learn something then learn something else and try to put the two things together.

M: and it’s all coming together now?

JL: It is, everything I’ve done is coming together now.

M: Tell me about that, because that’s why you’re back.

JL:  That’s why I’m back. Regarding Parkinson’s disease – we now have human pluripotent stem cells that can be turned into dopamine neurons, so all the things that were wrong with the early work I was doing in the late 80s I can now fix.

M: You’re independent in an academic setting now.

JL: Yes, I’m an academic with my own lab. I have the Parkinson’s history and I have the mouse embryonic stem cell history, which Austin and Rudolf share. You know it’s interesting people who come from a mouse embryonic background and then started working on human ES or iPS cells have been really annoyed that the human cells don’t act like the mouse cells. They’re much harder to grow. So both Rudolf and Austin have been trying to turn human pluripotent stem cells into cells like the mouse.

M: Is this kind of an internal debate?

JL: Yes, this is what they’re focused on now & intensely competing with each other over whether you can make human cells with the qualities of mouse cells. I’m not involved- I just went straight to human pluripotent stem cells and realized they were not going to be like mouse and lived with it.

M: Is that because of the quality and body of evidence in the mouse?

JL: Yes, the history is with mouse ES cells and the kind of things you can do with them. They’re much more robust than human pluripotent stem cells. Human embryonic stem cells have to be babied, but mouse ES cells you can pretty much leave in an incubator and they’re fine. The researchers have moved in the direction of trying to make hESCs be like that.

M: To perform better?

JL: Yes, so that then can take all those techniques they used in the mouse and now apply them to human. As I said, I’ve just bypassed that. My cells can become what I want them to become and that’s it – I’m done. They don’t need to be like mouse cells.

To continue, while I was still at Incyte I started a company and made a bunch of hESC derivations that were on George Bush’s original list.

M: From IVF donations?

JL: Yes, that’s right. I started a company, so I did it in my own company. There were 3 employees. I was the scientist and I had an assistant.

M: You had a number of lines. What ever happened to those lines?

JL: Well, they got acquired by another company and I have no idea, they’re probably still in the freezer somewhere. They never did anything with them. But it’s not important any more as there are so many lines out here. There are 300 lines or so on the NIH registry of lines that can be used in federal grants.

M: And they’re sufficient to do the science work?

JL: Yes. But my lab doesn’t work much on hESCs anymore. We work with iPSCs because they are equivalent to hESCs and you can get them from individual people. This is where my genome experience comes in because I learned sequencing and genomics when I was at Incyte, so I had an appreciation of the methods used to study the genomes of cells.

M: The translational aspect of what you’re working on is focused on Parkinson’s as a primary program?

JL: Yes. There are a lot of reasons for it. The person who came to me with the idea to do a therapy for Parkinson’s disease is the head of the movement disorders clinic at Scripps Health, which is across the street from me. She thought there ought to be a stem cell therapy for Parkinson’s disease and together we did fundraising to start the project. We want to do a personalized therapy, an iPSC therapy, and genomics is very important as we want to have quality control throughout the process of developing a therapy.

M: This is your approach to it?

JL: Yes. One of the things we’ve learned from studying pluripotent stem cells is that they acquire mutations if they spend a lot of time in culture. You don’t want to put cells with dangerous mutations into people, so that’s where genomics expertise comes in, essentially in assuring the quality control of the cells we want to transplant.

M: Is that the same risk factor in regard to hESCs?

JL: Yes, they will do the same thing. In fact everything we’ve done to date shows that iPS and ES cells are identical. Our approach has been to analyze lots of cell lines, not just one, to learn what to expect from cell lines in general. Almost everything we’ve done was done on 100s of cell lines so we can come up with general principles.

M: I remember you putting out a paper on this recently that was very exhaustive – 2 years of work

JL: Yes, 2 years of cell culturing. The scientist I worked with on that is here at the meeting – I’m going to take him to lunch tomorrow. The whole idea was to try to come up with things that were generalizable to cell lines and different conditions.

M: So if you use 1 cell line that is on the edge of a uniform grouping that will be different than if you select and productize something else within that sequence?

JL: Yes

M: and that’s where we’re at?

JL: Yes, right now. Here’s the challenge. If you have different cell lines we know they’ll have some diversity. They act a little bit differently, a lot due to the personal genomes, of course. The challenge we have is to develop technologies and quality control methods to allow us to know how every one of those cell lines becomes the same thing every single time.

M: Is that a far reaching goal?

JL: I think it’s actually going to work pretty well. A lot of this has been developed already. That’s been a high priority all along. Some people think it’s never going to work but I don’t believe that.

M: Is RNA a part of that process?

JL: Yes, absolutely.

M: So the work presented recently by Yamanaka will factor into this.

JL: Yes. The way we make the cells is important – we’ve investigated that. How you reprogram the cells so that the cells aren’t harmed.

M: Is that Sendai?

JL: Yes, that’s right. We’ve done whole genome sequencing on a lot of cell lines and we’ve discovered that using Sendai vectors for reprogramming is benign. The other methods are also benign, which is important to keep in mind.

M: So looking at this from a cost perspective, autologous patient specific treatments are highly personalized but are highly expensive. Is that part of the process strategically?

JL: Yes, that’s right. It’s part of the process. There’s a lot of discussion on personalized therapy and whether it’s worth the cost.

M: Of course, if it costs $1 million dollars how many people can actually be treated?

JL: Well, more than you think. It turns out for cancer treatments the amount of money that people are paying is similar.

M: Is this about annuities, is that where we’re going?

JL: No. Somebody needs to figure out how to have insurance reimburse for therapies. Right now we’re not worried about that yet. But I can see how it’s going to work because the work that’s being done now with T-Cells, CAR-T therapeutics.

M: I wrote about that 3 years ago.

JL: There you go. That’s about how much it costs for what I’m doing and yet there are multiple companies developing this technology now that it’s been shown to work.

M: There are many now but there were none before.

JL: Well I remember the first time I heard about it I thought I had no idea you could do that. I didn’t know the immune system could do that.

M: The immune system is a powerful force to employ.

JL: Yes it is, and that’s one of the reasons we’re using autologous therapy. We want the cells to be matched and don’t want them to be rejected.

M: Isn’t there a movement towards allogeneic?

JL: It’s hard to say. Yes, probably because of the effort in characterizing cells, but let me put it this way. As soon as we demonstrate we can make the same cells from 8 different patients and they all work, then the story’s over. Autologous therapy and the price point will be worth it. It will be like CAR-T therapy. It will be what you have to do for the best possible therapy.

M: Wouldn’t you want to test an allogeneic source?

JL: I don’t want to as others are doing it. I’m going to let them go ahead and do it.

M: and who are those others?

JL: The Studer Lab in the US. Actually there’s one other autologous therapy which is being done in Japan by Jun Takahashi.

M: Coming out next year.

JL: Yes, his and my projects are very similar. We’re trying to collaborate but I don’t think it’s going to work, as it’s almost impossible to exchange materials between the US and Japan.

M: Really I thought we were friends in many ways.

JL: We are but when it comes to scientific IP, it’s very hard.

M: They do want to license a lot of their underlying technology, Japan Academia, Healios.

JL: and I would be licensing it if I were a company but I don’t have to as an academic and that’s another strategy of mine.

M: Don’t they have underlying patents?

JL: Oh yes, and if I decide to commercialize what I develop I’m going to have to license patents from Japan. But I’m going to worry about that later. I know a bit about patents too.

M: I remember that.

JL:  I think we have a good strategy. The thing is you can never be certain, but the science makes sense, the strategy makes sense.

M: To be clear on this patent issue – you don’t need a license to do clinical trials.

JL: No. I don’t need a license to develop anything, as long as I’m an academic and I’m not commercializing it,

M: The concept is Japan Academia is licensing for research purposes because they deliver a package.

JL: Yes – and I don’t need it yet because I’m a non-profit. They will license their technology for research purposes to companies but they won’t let anybody sell the iPS cells.

M: The process of development can happen independently using Sendai without a license.

JL: Yes that’s correct. I was in biotech and I was affected rather negatively by patents at times. I remember this very clearly: my friends and I wanted to challenge the WARF patents that gave them ownership of all human embryonic stem cells, and we worked on this for many years. The patents expired just before we asked the Supreme Court to hear the case for overturning the patents, and they declined to hear it. When I became an academic, as I liked to say to the WARF attorneys as many times as I could, I had the freedom to operate and not require a patent from them to do embryonic stem cell research. Our patent challenge was very interesting and very educational; as a result of our challenge, WARF narrowed the claims of their patents to limit them specifically to embryonic stem cells. Their original patents claimed all pluripotent stem cells, so if we hadn’t challenged the patents, they could have retroactively claimed iPSCs.

M: There are a few words in there which are specific to embryo derived.

JL:  What happened was, we challenged the patents, the patent office rejected all of them, and in order to get the patent office to reinstate them they had to change the language for their primary patent.

M: It was their intent in the first place.

JL: I think we caught them by surprise. I met some really great people as a result of the patent challenge. The attorney who was with me was the same attorney who brought the challenge to the Myriad patents. He was at the Supreme Court for that case and I went to the Court to watch them argue that case.

M: Interesting isn’t it?

JL: It was fascinating

M: The legal system is a world apart

JL: It’s so bizarre

M: Somewhat like the science world?

JL: No, well in theory yes. What really struck me was the fact that the Supreme Court justices, and I think lay people, need metaphors in order to understand science.

M: They do and communication from science to the world is vital as the boxed view of old school scientists just doing experiments to publish needs to change.

JL: I don’t know why people would do that, to tell you the truth.

M: I think there is a value. My curiosity brought me here. So I think there’s a great value in curiosity and the maintenance of that throughout your life

JL: I agree.

M: I like that analogy the Salk Professor, Rusty Gage, presented. He spoke of a running an experiment where brain cells develop due to vitality, even in disease states. I’m not sure how a Parkinson’s patient can actually get on a treadmill but….

JL: Exercise does help Parkinson’s patients, physically and mentally. Our funding mechanism is patient advocacy based, a partnership with patients.

M: I’m not aware of your funding mechanism.

JL: The funding comes from a private foundation that we started to fund this project

M: I remember this – just recently you did a drive. How did that go?

JL: It’s gotten enough money to get us to the pre-IND stage.

M: Did CIRM ever come in?

JL: CIRM will come through the next round, I believe. We’re certainly going to apply for CIRM money. We’ve been working up to this for a long time. The patients have been going to CIRM meetings so we can educate the panel about the importance of this.

M: How far are you away from the IND

JL: About 2 to 3 years

M: That’s pretty similar to some of the others – Malin Parmer for instance mentioned 2018. Of course the Japanese are coming on fast next year.

JL: They’re on a fast track – there are some positives and negatives about that.

M: Tell me about that. There is I guess a Japanese societal push, an industrial push. They have a tendency to like to do that in industry and it’s been beneficial in the past. Do you see that as a mechanism to dominate?

JL: Yes, absolutely.

M: and will it open up things potentially or will there be a downfall?

JL: The good thing as far as I’m concerned, is if Jun Takahashi gets his therapy through the regulatory agency, he gets to transplant his cells to people and they’ll be doing that before I do. It’s unlikely that our FDA will let me do it sooner. So if nothing bad happens to the patients in Jun’s study, that will help me. However, if somebody else pushes through a therapy because of this fast track, a scientist who are not as careful as Jun Takahashi, there could be issues. Stem cell therapy, just like everything else, if it is strongly promoted, can have setbacks. In Japan we saw what happened with the STAP problem. As soon as there’s a lot of pressure from the Japanese society and Government to move forward there are going to be people that make mistakes. There will be people who are not careful.

M: Masayo Takahashi is trialing iPS cells.

JL: Yes and she has published preclinical work. Essentially she is trying to show equivalency of iPS to ES cells. I think that’s very important, as the FDA is still worried about iPS cells.

M: They are it seems. There was some planning to file an IND for Platelets.

JL: Yes.

M: Do you know that story?

JL: I do, yes.

M: Will you tell it?

JL: I probably can. I can publicly say I was a consultant for them [Ocata/ACT] and that I attended their pre-clinical meeting as a consultant. So I know about the reaction of the FDA about that.

M: This was back 3 years ago?

JL: Yes, I think 2 to 3 years

M: 2013

JL: It turned out that I wasn’t really necessary as an advisor. I didn’t say a word but it was fascinating to see the FDA’s response.

M: The concerns they had were GMP compliance related.

JL: Yes, but they’re getting over that. They’ve approved ES cells that were not made with the intent of using them for therapy. One of the cell lines that they approved was derived in 1998 using bovine serum, which was a concern before the safety trials showed that it wasn’t important.

M: Yes even the Ocata/ACT cell line comes from some time ago on MEF.

JL: Yes, and I’m not concerned about that. There are some issues with using xeno reagents but they are really related to whether you’re making the cells make the wrong kinds of sugars. If you were to put mouse embryonic cells or mouse iPS cells on mouse embryo fibroblasts (MEF), viruses could be transferred into the cells, but this doesn’t happen with human pluripotent stem cells. Nobody has ever shown any kind of viral infection in human cells that comes from the MEFs.

M: That’s why the safety is intact.

JL: Yes, exactly. The process is to imagine bad things that might happen, then prove that they don’t happen.

M: It’s only a transitory process as well.

JL: Yes, you’re not putting mouse cells into people. But you’re also not infecting the cells so there’s no lasting change.

M: There are a lot of other technologies that are far more dangerous – virus delivery for instance.

JL: Yes, of course, and viruses used for early gene therapy have actually been shown to be dangerous in some cases.

M: There have been a lot of adverse events and people have actually died in the CAR-T trials and no one talks about it.

JL: That’s right.

M: My feeling is the xeno movement is a good thing for standardization and some of the work shown here, the BioLamina work and the Thermo Fisher work, these are very good protocols that need to be adopted and the expansion occur.

JL: That’s fine. As long as they are necessary and they work well, I don’t really care what methods are needed. I’m not too worried about the xeno issue because the cells won’t be interspecies transplants.

M: Are they requiring it now, is that the new standard?

JL: Not yet, no. We just had a meeting with our regulatory consultant a couple of weeks ago, but of course you never know.

M: So when the Israelis and BioTime and others in the field are touting the xeno-free, it’s just marketing?

JL: Perhaps, but don’t let’s push that too far; I mean the FDA is never perfectly predictable and they could decide at any time that they think it’s dangerous to have xeno reagents.

M: But the products will be approved without a line switch.

JL: Right, that’s right.

M: What are the programs in the pluripotent space you think will reach the market within the next 5 years?

JL: Obviously there’s a lot of interest in the reagent business and there are a lot of companies that are joining in, especially in Japan. I really didn’t realize how much was involved in Japan in creating reagents for taking the cells to the clinic.

M: ReproCell?

JL: Yeah, ReproCell and others.

M: Takara?

JL: Yes. I’m giving a talk at an innovation showcase tomorrow for another Japanese company. One of my friends asked me to do it for him because he can’t make it here. They’re a very large chemistry company. They’ve been in business a long time and now they want to start to apply what they’ve done to stem cells.

M: Interesting how some of the non-scientific power houses in Japan are involving themselves now. A change in strategy perhaps. Digital is affecting their main lines of business and there’s an opportunity.

JL: Absolutely. They have a lot of bandwidth. Fuji Film just bought Cellular Dynamics. I mean you’re not making film anymore so you might as well make stem cell reagents.

M: I don’t want to press on the point of who’s going to come to market soon but success needs to be translated and your view on early access as being a component of adoption, proof of clinical concept, is that in your view an essential part of regulatory review & language?

JL:  Japan has fast tracked cell therapies, but I think our FDA is not going to fully adopt such regulations. Perhaps this is because the Japanese regulatory authorities have decided to trust their scientists more than the FDA trusts us.

M: In my view Japan also has a symbiotic relationship with the other parts of the system, you know, it works all together – the insurance, the legal, the funding, the university/academic and business community.

JL: I know, it’s really amazing. I’m really envious.

M: Anything else on the program front? I wanted to talk about the Zoo work.

JL: I know that’s what you actually wanted to talk to me about.

M: Yes, it was fascinating that you’re doing that work.

JL: Yes, we decided that we should try to reprogram endangered species cells, so in 2011 we published a paper to say we can – Rhinos, using human technology. We hope to use those cells to help restore the species.

M: The egg/sperm combination?

JL: All that stuff is coming. At that time we just made iPS cells from the animals and the project lay dormant for a while because the zoo we were working with thought it was a bit little creepy, too Jurassic Park. They’ve now decided to embrace it.

M: Weren’t there a number of international groups working on that before?

JL: Yes but not a lot, not in this particular thing. There was a group in Australia that was reprogramming other animals.

M: Interestingly in Spain also.

JL: Yes, that was different though, replacing one animal with another in a habitat.

M: Using an animal to host?

JL: Well they’ve done that too. The essence of our approach with endangered animals is to use the technologies that have been developed for mouse and for humans to make gametes out of the iPS cells. Then use IVF technology, that is also in development for these animals, and have a surrogate host that we’ll be able to put the embryos into and regenerate the species. Just a small thing! I’m doing this with the Northern White Rhino, as there are only 5 of them left. There’s only one male and the females I think, with one exception, are beyond reproductive age and they’re dying. [Note: another Northern White Rhino died in late July, so now there are 4].

M: So how would you approach that?

JL: The Southern White Rhino has a very similar reproductive cycle. The Northern White Rhino are a different species but they’re very similar. No one really knows if you can cross them yet. We want to make the gametes from the Northern White Rhino, inseminate the eggs in a culture dish and transfer the embryos to a Southern White Rhino.

M: The egg would come from the endangered species also?

JL: Yes, from the pluripotent stem cells.

M: Both gametes.

JL: Yes both gametes would be produced from iPS technology.

M: Have you proven that yet?

JL: No, we had no money, so we essentially have been generating more iPS cells and we’re getting better at it. But now there’s going to be an investment, that’s what they tell me. The zoo has decided.

M: Which zoo is that?

JL: The San Diego Zoo.

M: Wonderful.

JL: They’ll be announcing that when they want to, it’s not up to me.

M: Very good, I wish you luck with that.

JL: Thanks, it’s one of those things which seemed obvious at the time.

M: Well worth doing.

JL: Yes, it is worth doing and it was just a matter of timing. I think a lot of this is like that. If you’re too ahead of people’s understanding of what you’re doing then it will just sit there dormant until they understand it.

M: I think in most fields if you’re pioneering something you have a responsibility to educate.

JL: Yes but people also have to accept it. I’ve seen a lot of changes in the stem cell world since we started this in 1998 so it’s been a while.

M: The %s are way higher now.

JL: Yes, they’re higher, that’s right, and it does have to do with education and our patient advocacy approach means we educate patients and the patients educate other people because they’re motivated. They may have not wanted to be scientists but they’re driven to understand it because they want to get cured, they want to get treated.

M: Thank you Jeanne

JL: Ok


Ref: Parkinson’s review by EuroStemCells

My new ‘neighbor’ in Sacramento: a fat stem cell clinic

Thomas A. GionisFor years I’ve been writing about stem cell clinics that sell non-FDA approved stem cell “treatments” to vulnerable patients right here in America.

These clinics have been sprouting up like mushrooms across the US and their numbers may be above 200 today overall. As a result perhaps it was inevitable that one would arrive in a locale near me.

Tomorrow, July 11, reportedly the Irvine Stem Cell Treatment Center will open a Sacramento, CA branch. The doctor there will apparently be Thomas A. Gionis (picture from press release). This private, for-profit clinic has no affiliation with UC Davis School of Medicine in Sacramento where I’m located.

The stem cell clinic Sacramento branch will sell transplants of fat stem cells in the form of something called stromal vascular fraction or SVF, which I believe is almost certainly a drug. To my knowledge this clinic and the large chain that it belongs to called Cell Surgical Network (CSN), do not have FDA approval to use SVF.

Both publicly and to me on this blog, CSN continues to argue that it doesn’t need FDA approval (herehere and here), but recent FDA draft guidances sure suggest otherwise in my view. Of course if the FDA never takes action on the use of SVF then how are we all supposed to interpret that? Without FDA action or finalized guidelines, is it formally possible that the FDA could back down on SVF?

This clinic will reportedly sell SVF to treat a dizzying array of conditions having nothing to do with fat:

“Emphysema, COPD, Asthma, Heart Failure, Heart Attack, Parkinson’s Disease, Stroke, Traumatic Brain Injury, Lou Gehrig’s Disease, Multiple Sclerosis, Lupus, Rheumatoid Arthritis, Crohn’s Disease, Muscular Dystrophy, Inflammatory Myopathies, and Degenerative Orthopedic Joint Conditions (Knee, Shoulder, Hip, Spine).”

To me as a scientist the use of SVF to treat all these very different conditions does not make good common sense.

It would also seem arguably to be quite likely be considered “non-homologous use” by the FDA, a standing that would also automatically make this a drug requiring FDA pre-approval. Non-homologous use means using a biological product of a certain kind that is not homologous (not the same or similar in origin) to the tissue being treated. For example, fat is not the same as the brain or other central nervous system tissue that is involved in several of the conditions on the clinic menu. Same goes for cardiac muscle, airways, etc.

The use of a non-FDA approved product in a largely non-homologous manner increases risks for patients. Note that these stem cell transplants are also very expensive with little evidence in the way of published data of benefit.

The CSN stem cell clinic in Sacramento will be located at the New Body MD Surgical Center, just about 10 minutes from my office. I plan on paying them a visit at some point. Let’s see how that goes. Will they let me in?

Yamanaka Interview on Clinical Use of Pluripotent Stem Cells

Dr. Shinya Yamanaka

Dr. Shinya Yamanaka.                                           Photo from CiRA, Kyoto University

I invited Nobel Laureate Shinya Yamanaka to do an interview on the future of clinical translation of induced pluripotent stem cells (iPSC).

He provides some intriguing new insights into the iPSC field and the broader stem cell arena.

PK: The Takahashi Team’s active Clinical Study using iPSCs to make RPEs to treat Macular Degeneration has generated a great deal of excitement. Can you please share your perspectives on the importance of this work and the team involved? 

SY: This is the first study to apply iPSC technology to human care. This is a very important study, because if it succeeds it will show that iPSCs can be safely used in humans and also their potential for cell transplantation treatment. We collaborated with Dr. Masayo Takahashi of RIKEN CDB by evaluating the safety of the iPSCs and iPSC-derived cells that were used for the cell transplantation. She is an excellent researcher, and I am not surprised that her team is the first to have succeeded in this transplant.

PK: Any cutting edge investigational clinical work such as this has some risks. Could you please comment on the potential risks in this iPSC trial? Are there some elements here such as preclinical data, the number of cells used, or the target tissue of the eye that lower risks?

SY: One of the major concerns is whether transplanted cells such as the RPE sheets will cause tumors. In our collaboration with Dr. Masayo Takahashi’s team, we evaluated the safety of iPSCs and iPSC-derived cells by genome and epigenome analysis. While we minimized the risk to a level acceptable for clinical trials, we really cannot confirm how the cells will respond until we actually do experiments with humans, which is why this project is so important. One advantage of treating age-related macular degeneration is that it is easy to detect any abnormalities in the eyes, which is why the disease is a good starting model for iPSC-based treatment.

PK: As the inventor of iPSCs did you imagine 7-8 years ago that a patient in a clinical study in 2014 would already have received an iPSC-based treatment? How was this rapid translation from bench to bedside possible?

SY: 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.

The rapid transition is because many bright and passionate people are in the iPSC field. The funding and infrastructure provided by the Japanese government is also a major factor, as these have encouraged excellent scientists to enter the field.

PK: We are also starting to hear more about Dr. Jun Takahashi’s Team’s important work towards using iPSCs to treat Parkinson’s Disease. Can you please tell us more about that?

SY: Prof. Jun Takahashi’s team at CiRA is working on cell therapy for Parkinson’s disease, aiming to transplant iPSC-derived dopaminergic neural progenitor cells into PD patients’ brains. Early results suggest this treatment can be effective, and his team has established the protocol for transplantation. They are now focusing on validating its safety using monkey models. We hope his work will soon reach the operating room within the next few years.

PK: What other clinical applications of iPSC technology are in the works and that might begin clinical studies in the next few years?

SY: There are two major clinical applications of iPSCs, namely regenerative medicine and drug discovery. CiRA has a number of researchers working on either or both. For regenerative medicine, Prof. Koji Eto at CiRA is working on generating platelets via iPSCs, and we expect this will also proceed to clinical research in a few years. Besides work at CiRA, a team at Keio University has a plan to conduct clinical research on patients with acute spinal cord injury in four to five years, while Osaka University and Keio University hope to transplant iPSC-derived cardiac myocytes into patients with heart diseases within a few years. CiRA is collaborating with these teams as well.

Regarding drug discovery, you may have heard recently of CiRA’s Prof. Noriyuki Tsumaki’s paper about statins effects on bone growth, which was published online in Nature last month.

PK: Some in the media are taking about a certain tension between clinical iPSC work in Japan and clinical iPSC work in the US. Do you believe such a tension exists and if so, why? What does it mean for the iPSC field overall?

SY: I am not sure what “tension” means. I understand that both competition and collaboration exist between the US and Japan.

PK: How do you view hESCs today? Are there hESC clinical trials or potential applications that are of particular interest? What is your view of the argument by some that hESC are no longer needed?

SY: Human ESC was a great discovery for regenerative medicine and also instrumental to the discovery of iPSC and the type of medical treatments we are aiming to apply iPSC. At the same time, the ethical issues that hESC possess mean that as iPSC technology improves, hESC will be less needed. Still, iPSC is a new technology, and its safety and efficacy still needs to be confirmed. In addition, there may be some therapies for which hESC are better than iPSC. Thus, I think basic and clinical research of hESC is also important and should be done in parallel with iPSC research.

PK: What excites you most about the stem cell/regenerative medicine field right now today?

SY: I am excited about the possible number of people treated with iPSCs. This field has great potential to provide treatments for currently incurable diseases. Hopefully, within 5 years, we will refer to Dr. Masayo Takahashi’s AMD work as just one of many patient studies using iPSCs.

PK: Where do you see the iPSC field and the broader stem cell field in say 5-10 years?

SY: It is pretty amazing how much it has changed in the past years, so predicting the next 5-10 years is very difficult. I certainly hope we will see more diseases being treated with iPSC and related technologies such as direct reprogramming. I also hope that iPSC will be used more widely and routinely in drug development.

PK: What advice would you give to young scientists today who are excited about a career in stem cells/regenerative medicine?

SY: Through biomedical research, you could help thousands of patients in the future. Stem cells provide unprecedented opportunities in stem cell therapy and drug development. Biology of stem cells itself is extremely interesting. I hope many young scientists will enter to this field.

Will Speedy A4M Stem Cell Course for Docs Put Patients at Risk?

They say a little knowledge is a dangerous thing. I say that a little stem cell training for MDs can potentially be a dangerous problem too.

A4M logo

I’ve been very concerned about self-proclaimed “stem cell training courses” for MDs.

These kinds of courses have claimed that over as short as a weekend (perhaps with golf) they fully prepare physicians to do stem cell interventions on patients. Such stem cell-related procedures can yield big profits for physicians, but what about the best interest of patients? Are the physicians also putting their practices at risk as well?

Now I see that the American Academy of Anti-Aging Medicine (A4M) has pushed the stem cell quick clinical training model to an extreme with a new 1-day stem cell training course. 

In fact in just 10 hours A4M claims its course will make doctors qualified to start treating patients right away.

This claim is explicitly stated in the course description (emphasis mine):

“Learn how to successfully incorporate and market stem cell treatments into your practice. The latest in stem cell theory and clinical trial research for all aspects of Regenerative Medicine, including embryonic, bone marrow-derived, adipose-derived, and platelet rich plasma will be covered. Attendees will leave the clinical training course with the skill and knowledge to treat patients immediately upon returning to their offices.

It’s an astonishing claim. Note that they also emphasize marketing stem cell treatments to patients too.

Is a 10-hour course all any MD really needs to start doing stem cell transplants on patients in a safe and effective manner?

I don’t think so. At least not in a responsible, careful manner. That particular claim for this course is very troubling.

What’s next I wonder? A 1-hour online course enabling doctors to supposedly immediately start treating patients with stem cells?

Who are the people involved in running this A4M course? The faculty listed for this course are the following: Sharon McQuillan MD, David Audley MS, Arnold Caplan PhD, Rafael Gonzalez PhD, Augusto Brazzini MD, Mark Holterman MD PhD, Adeeb Al-Zoubi MD PhD, Lora Brown MD, Howard Walpole MD, Neil Riordan PhD, and Elliott Lander MD PhD.

Even if the faculty are the top stem cell experts in the entire world, in just 10 hours they could not adequately prepare newbie stem cell docs to immediately go treat patients safely.

Another concern is that the course spans a host of conditions as well and there is little if any evidence that stem cells are safe and effective today for these diseases: Parkinson’s Disease, Diabetes, Musculoskeletal Repair and Regeneration, Heart Disease, Autoimmune diseases, and erectile dysfunction.

The bottom line is that this A4M course seems to me to be all about quickly enabling doctors who are newbies to the stem cell world to make money by doing stem cell interventions. I suppose the course may also make A4M itself money too via course registration fees.

What we really need instead are comprehensive physician training programs of the kind I proposed in 2013 that span a year and thoroughly cover all the keys issues: technologies, bioethics, consent, patient rights, risks, regulatory complexities, etc.

Thorough physician training is in the best interests of the field, physicians, and patients.