Parkinson’s is a neurodegenerative condition. This means that cells in the brain are being lost over time. Any ‘cure’ for Parkinson’s is going to require some form of cell replacement therapy – introducing new cells that can replace those that were lost.
Cell transplantation represents one approach to cell replacement therapy, and this week we learned that the Japanese regulatory authorities have given the green light for a new cell transplantation clinical trial to take place in Kyoto.
This new trial will involve cells derived from induced pluripotent stem cells (or IPS cells).
In today’s post we will discuss what induced pluripotent stem cells are, what previous research has been conducted on these cells, and what we know about the new trial.
Source: Glastone Institute
The man in the image above is Prof Shinya Yamanaka.
He’s a rockstar in the biomedical research community.
Prof Yamanaka is the director of Center for induced Pluripotent Stem Cell Research and Application (CiRA); and a professor at the Institute for Frontier Medical Sciences at Kyoto University.
But more importantly, in 2006 he published a research report that would quite literally ‘change everything’.
In that report, he demonstrated a method by which someone could take a simple skin cell (called a fibroblast), grow it in cell culture for a while, and then re-program it so that it would transform into a stem cell – a cell that is capable of becoming any kind of cell in the body.
The transformed cells were called induced pluripotent stem (IPS) cell – ‘pluripotent’ meaning capable of any fate.
It was an amazing feat that made the hypothetical idea of ‘personalised medicine’ suddenly very possible – take skin cells from anyone with a particular medical condition, turn them into whatever cell type you like, and then either test drugs on those cells or transplant them back into their body (replacing the cells that have been lost due to the medical condition).
Personalised medicine with IPS cells. Source: Bodyhacks
IPS cells are now being used all over the world, for all kinds of biomedical research. And many research groups are rushing to bring IPS cell-based therapies to the clinic in the hope of providing the long sort-after dream of personalised medicine.
This week the Parkinson’s community received word that the Pharmaceuticals and Medical Devices Agency (PMDA) – the Japanese regulatory agency that oversees clinical trials – have agreed for researchers at Kyoto University to conduct a cell transplantation trial for Parkinson’s, using dopamine neurons derived from IPS cells. And the researchers are planning to begin their study in the next month.
In today’s post we are going to discuss this exciting development, but we should probably start at the beginning with the obvious question:
What exactly is an IPS cell?
In 2006, this study was published:
Title: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
Authors: Takahashi K, Yamanaka S.
Journal: Cell. 2006 Aug 25;126(4):663-76.
PMID: 16904174 (This article is OPEN ACCESS if you would like to read it)
In this study, Shinya Yamanaka‘s team started with the hypothesis that proteins which are important to the maintenance of embryonic stem cells (the cells that give rise to all of the cells in your body) might also be able to cause an embryonic state in mature adult cells. They selected twenty-four proteins that had been previously identified as important in embryonic stem cells to test this idea. They used re-engineered viruses to deliver these proteins to mouse skin cells. The viruses were emptied of all their disease causing properties, and could thus function as very efficient biological delivery systems.
The skin cells were genetically engineered in such a fashion so that only cells in which reactivation of the embryonic stem cells-associated protein, Fbx15, would survive the testing process. If Fbx15 was not turned on in the cells, over time they would die. When the researchers infected the cells with all twenty-four embryonic stem cells genes, remarkably some of the cells actually survived and began to divide like stem cells.
In order to identify which proteins were necessary for the reprogramming, the researchers began removing one protein at a time from the pool of twenty-four. Through this process, they were able to narrow down the most effective proteins to just four: Oct4, Sox2, cMyc, and Klf4, which became known as the Yamanaka factors.
This new type of cell is called an induced pluripotent stem (IPS) cell.
And in acknowledgement of this amazing bit of research, in 2012 Prof Yamanaka and Prof John Gurdon (University of Cambridge) were awarded the Nobel prize for Physiology and Medicine for the discovery that mature cells can be converted back to stem cells.
Prof Yamanaka and Prof Gurdon. Source: UCSF
Prof Gurdon achieved a similar feat to Yamanaka’s work in 1962 when he removed the nucleus of a fertilised frog egg cell and replaced it with the nucleus of a cell taken from a tadpole’s intestine. That is to say, the nucleus of a mature cell was placed into a frog egg cell, and guess what happened? The modified egg cell then grew into an adult frog! This fascinating research proved that the mature cell still contained the genetic information needed to form all types of cells.
EDITOR’S NOTE: I do not want to be accused of taking anything away from Prof Gurdon’s contribution to this field (which was great!) by not mentioning his efforts here. For the sake of saving time and space, we are focusing on Prof Yamanaka’s research as it is more directly related to today’s post.
Making IPS cells. Source: learn.genetics
As I suggested above, the amazing discovery of IPS cells has opened new doors for biological research and provided us with incredible opportunities for therapeutic treatments. For example, we can now take skins cells from a person with Parkinson’s and turn those cells into dopamine neurons which can then be tested with various drugs to see which treatment is most effective for that particular person (personalised medicine in it’s purest form).
Some of the option available to Parkinson’s disease. Source: Nature
Some of those dopamine neurons could also potentially be transplanted back into the person – into the brain to replace the lost dopamine neurons. This process would hopefully reduce the need for medication that suppresses the immune system, because the body would recognise the cells being transplanted as ‘self’ (or derived from the person being transplanted).
Imagination is literally the only limiting factor with regards to the possible uses of IPS cell technology.
How do IPS cells differ from embryonic stem cells?
This is very simple:
IPS cells are engineered in a laboratory, while embryonic stem cells are a natural form of pluripotent stem cell – derived from a very early stage embryo.
Embryonic stem cells in a petridish. Source: Wikipedia
The process of collecting embryonic stem cells begins with a fertilised female egg cell. The egg cell will divide, to become two cells, then four, eight, sixteen, etc. Gradually, it enters a stage called the ‘blastocyst’, which is a small ball of cells. Inside the blastocyst is a group of cell that are called the ‘inner stem cell mass’, and it is these cells that can be collected and used as embryonic stem cells.
The process of attaining embryonic stem cells. Source: Howstuffworks
Although they differ in their origins, IPS cell and embryonic stem cells both share many similarities, such as the ability to become any cell inside your body.
Are there other research groups using embryonic stem cells for cell transplantation in Parkinson’s?
Yes, there are, and we recently discussed and summarised some of those efforts in another post (Click here to read that post). In this post we are going to focus on the Kyoto research team.
So who are the Kyoto research team?
The Kyoto research team is led by Prof Jun Takahashi:
Prof Jun Takahashi. Source: gforce-pd
He is the Head of Department of Clinical Applications at the Center for iPS Cell Research and Application, Kyoto University
He and his research team have a long history of working with IPS cells, particularly in the context of models of Parkinson’s:
Title: Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson’s disease.
Authors: Kikuchi T, Morizane A, Doi D, Onoe H, Hayashi T, Kawasaki T, Saiki H, Miyamoto S, Takahashi J.
Journal: J Parkinsons Dis. 2011;1(4):395-412. doi: 10.3233/JPD-2011-11070.
This study was one of the first investigations of IPS-derived dopamine neurons being transplanted into both a mouse model of Parkinson’s and a primate model of Parkinson’s. The researchers found that the dopamine neurons survived in a monkey brain for at least six months (the length of the study).
More recently, the Kyoto team have been trying to better purify the population of cells being transplanted:
Title: Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1
Authors: Samata B, Doi D, Nishimura K, Kikuchi T, Watanabe A, Sakamoto Y, Kakuta J, Ono Y, Takahashi J.
Journal: Nat Commun. 2016 Oct 14;7:13097.
PMID: 27739432 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers utilised a double selection strategy for identifying the cells to transplant into both a rodent model of Parkinson’s and (again) a primate model of Parkinson’s. The transplants resulted in a significant improvements in motor behaviour in the animals, without any signs of tumor formation.
These efforts all lead to a long-term study of transplanted IPS-derived dopamine neurons in a primate model of Parkinson’s:
Title: Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model.
Authors: Kikuchi T, Morizane A, Doi D, Magotani H, Onoe H, Hayashi T, Mizuma H, Takara S, Takahashi R, Inoue H, Morita S, Yamamoto M, Okita K, Nakagawa M, Parmar M, Takahashi J.
Journal: Nature. 2017 Aug 30;548(7669):592-596.
In this study, the researchers transplanted human IPS cell-derived dopamine neurons into a primate model of Parkinson’s and then followed some of the animals over 2 years. Not only did the transplanted cells help to restore normal function in these animals, but there was no sign of any tumors. In this study (and others – click here for an example), the Kyoto team focused a lot of effort on limiting the immune system response to the transplanted cells, by carefully selecting the cells to be transplanted (more on this below).
And Prof Takahashi’s research team has also spent a lot of time making IPS cells from people with Parkinson’s and testing their ability to be transplanted:
Title: Idiopathic Parkinson’s disease patient-derived induced pluripotent stem cells function as midbrain dopaminergic neurons in rodent brains.
Authors: Kikuchi T, Morizane A, Doi D, Okita K, Nakagawa M, Yamakado H, Inoue H, Takahashi R, Takahashi J.
Journal: J Neurosci Res. 2017 Sep;95(9):1829-1837.
Interestingly, in this study, the researchers found that there was no significant vulnerability between dopamine neurons generated from IPS cells from people with idiopathic (or spontaneous) Parkinson’s compared to IPS cells from healthy controls. Both sets of cells survived and functioned in a rodent model of Parkinson’s, as well as a genetically engineered mouse which produces too much Parkinson’s-associated alpha synuclein.
Needless to say, Prof Takahashi and his team have a great deal of experience transplanting dopamine neurons derived from IPS cells into models of Parkinson’s.
And they are now keen (and confident) to take this method into clinical testing.
So what do we know about the new trial?
Prof Jun Takahashi (speaking) and colleagues. Source: Japantimes
Information provided by Kyoto University (Click here for the study website) and the Japanese media has indicated that this Phase I/II clinical trial aims to investigate the safety and efficacy of transplanting human IPS cell-derived dopaminergic progenitors into the brains of people with Parkinson’s (what stage of PD has not been disclosed). The study will involve just 7 participants, and it will be starting very soon (recruitment began the day of the announcement).
Physicians at Kyoto University Hospital will drill a 12-mm (0.5-inch) hole into the skull of the participants and 5 million of ‘dopaminergic precursor cells’ (derived from IPS cells) will be injected into a region of the brain called the putamen. This is one of the main regions of the brain where the dopamine neurons release their dopamine. The image below demonstrates the loss of dopamine (the dark staining) over time as a result of Parkinson’s (PLEASE NOTE that the time scale presented here varies from person to person):
The loss of dopamine in the putamen as Parkinson’s progresses. Source: Brain
In cell transplant procedures for Parkinson’s, multiple injections are usually made in the putamen, allowing for deposits in different areas of the structure. These multiple sites allow for the transplanted cells to produce dopamine in the entire extent of the putamen. And ideally, the cells should remain localised to the putamen, so that they are not producing dopamine in areas of the brain where it is not desired (possibly leading to side effects).
Targeting transplants into the putamen. Source: Intechopen
One important feature of this new IPS cell clinical trial is that rather than making patient-specific IPS cells (that is IPS cell unique and specific to each patient), the IPS cells being used in the trial are being “created using cells from people who have types of immunity that make them less prone to transplant rejections” (Source).
Several years ago, Kyoto University launched the “Stock Project”. This was an initiative to generate IPS cells that could be transplanted into a lot of people without generating an immune response. It was estimated that just 50 lines of carefully selected IPS cells would cover 73% of the Japanese population by the matching of three types of immune system markers (HLA-A, B, and DR – Click here to read more about this).
Presumably for this first study (I am speculating here for the purpose of discussion) the Kyoto team have generated IPS cells that have little or no human leukocyte antigen (HLA). HLA is a protein that is present on the surface of cells, and it is recognized by the cells of the immune system (such as T-lymphocytes). Proteins like HLA play a crucial role in the immune response after the transplantation of foreign (‘not self’) cells. Using IPS cells with no HLA will hopefully make it less likely that the cells will be rejected by the immune system, giving the cells a better chance of surviving long term.
In addition to using ‘immune system safe’ cells, the patients will also be treated with a drug called tacrolimus which is a drug that suppresses that immune system, dampening down any immune response and giving the cells the best chance of success.
The participants in the study will be followed and assessed for 2 years post transplantation.
The researchers are aiming to develop the method as a new treatment that will be covered by national health insurance program in Japan, making it available to a large number of people affected by Parkinson’s. This is a noble gesture, one that possibly also acknowledges the enormous investment that the Japanese nation has made in the IPS technology.
How can I get involved with the trial?
The study is only open to people who live in Japan and are covered by the Japanese health insurance scheme.
The University of Kyoto has set up a recruitment page for the trial (Click here to see that page), but some translation will be required.
Are future trials planned?
This is unclear at present and really depends on the outcome of this first trial. And the Japanese will be proceeding cautiously for reasons we will discuss shortly.
This is only the third human clinical trial using IPS cells approved in Japan. The first was launched in 2014, using retinal cells derived from IPS cells – the goal was to replace eye tissue damaged by a condition called age-related macular degeneration (or AMD). That study was led by Prof Masayo Takahashi of the RIKEN Center for Developmental Biology in Kobe – who just happens to be Prof Jun Takahashi’s wife.
Prof Masayo Takahashi. Source: Youtube
So you can see there is a great deal of IPS cell experience involved with this new trial.
While the AMD treatment was initially reported to be safe, there was one reported adverse event (Click here to read more about this). A report of that study was published last year (Click here to read the report).
The second IPS cell clinical trial approved by the Japanese regulators was only given the green light earlier this year. A team at Osaka University in Japan will be conducting an IPS cell–based clinical trial for ischemic heart disease.
Why would the Japanese be proceeding cautiously?
It should be noted that all of the research efforts taking stem cell based cell transplantation to the clinic are proceeding cautiously, because of the worry that just a few cells in the transplanted population will not turn into dopamine neurons, but rather something completely different. Given their pluripotent potential, this is an issue for both IPS and embryonic stem cell approaches to cell transplantation. And once something is transplanted into the brain it is very difficult to ‘un-transplant’ it.
Older cell transplantation methods, such as fetal tissue-based approaches do not have this problem, because the transplanted tissue is being dissected from neural tissue from embryos – those cells are all committed to being brain cells. But that approach has ethical issues as well as tissue supply problems.
Some readers may point out that an added worry with IPS cells is that the process of transforming the cells from skin cells to IPS cells can leave the transformed cells with random genetic mutations. This is probably less of a concern, however, because the Japanese have been screening all of their IPS cell lines for any cancer-associated genetic mutations, and rejecting anything that looks suspicious.
The Kyoto team are certainly very confident that their process of maturating and transplanting the IPS-derived cells is ready for going to the clinic. As we discussed above they have a great deal of experience with the technology, and they have not observed any tumors (or other oddities) in any of their preclinical transplantation results (out to 2 years post-transplantation), suggesting that the cells are safe to use.
Despite all of this, it is probably still wise to be cautious and prudent.
So what does it all mean?
In January, in our ‘Expectations for the year ahead’ post (Click here to read that post), one of the big expectations was a lot of clinical research activity kicking off around cell transplantation for Parkinson’s. And we have not been disappointed. Recently, Chinese researchers have announced the start of their clinical trial (Click here to read more about that), this week we have heard that the team in Kyoto is going to be starting in the next month, and in coming months we hope to hear about the commencement of a US-based clinical study being conducted by a biotech company called BlueRock Therapeutics.
In addition, there is the on going Transeuro study testing the fetal transplantation approach for Parkinson’s.
The Transeuro trial. Source: Transeuro
And there is a cell transplantation clinical study being conducted in Melbourne (Australia), by an American company called International Stem Cell Corporation (ISCO).
So all-in-all, there is a great deal of research activity on the cell replacement therapy front. And this is very encouraging to see after a long period of high hopes for this therapeutic approach.
Here at the SoPD, we will be keeping a close eye on the activities in Kyoto, and be listening in for any news when it becomes available. And we certainly wish the research team the best of luck with their new study.
Oh, and of course the IPS cell trial is not the only big thing happening in Kyoto! Next year is the 5th World Parkinson Congress will be held on the 4th-7th June 2019.
It will be a fantastic week of research presentations from world leading scientists, networking with members of the Parkinson’s community from all over the world, and raising awareness on a global scale about this debilitating condition.
And yours truly is planning to be there.
EDITORIAL NOTE #1 – It is important for all readers of this post to appreciate that cell transplantation for Parkinson’s is still experimental. Anyone declaring otherwise (or selling a procedure based on this approach) should not be trusted. While we appreciate the desperate desire of the Parkinson’s community to treat this condition ‘by any means possible’, bad or poor outcomes at the clinical trial stage for this technology could have serious consequences for the individuals receiving the procedure and negative ramifications for all future research in the cell transplantation field.
EDITORIAL NOTE #2 – the author of this blog is associated with research groups conducting the current Transeuro trial. He has endeavoured to present an unbiased coverage of the news surrounding the current clinical trials. Any opinions offered here are solely his own and do not represent those of any associated parties. He had not discussed the recent news with any colleagues before publishing this post.
The banner for today’s post was sourced from toursbylocals.